Triple Reuptake Inhibitors as Potential ... - ACS Publications

Perspective pubs.acs.org/jmc

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges Murugaiah A. M. Subbaiah* Department of Medicinal Chemistry, Biocon Bristol-Myers Squibb R&D Centre, Biocon Park, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India ABSTRACT: Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability. Medicinal chemistry efforts have resulted in more than 10 clinical candidates, although clinical candidates have failed to demonstrate superior efficacy compared to placebo or existing antidepressants. Hence, the successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability. TRIs also hold therapeutic potential for other indications, with four candidates under clinical development for attention deficit hyperactivity disorder, binge eating disorder, cocaine addiction, obesity, and type 2 diabetes. Clinical studies have indicated a lower abuse potential for TRIs than psychostimulants.

1. INTRODUCTION Depression is the leading cause of disability, diminished productivity, and dependent care globally, with an estimated 350 million people affected worldwide.1 Major depressive disorder (MDD) is a chronic and progressive mental disorder with heterogeneous etiology and symptoms and a high incidence of recurrence. MDD is a major risk factor for suicide, which is the tenth leading cause of death globally and is comorbid with several chronic diseases, including heart disease, stroke, diabetes, and cancer. It is estimated that about 10% of the US population are being treated with antidepressants for either depression or related disorders.2,3 Current pharmacotherapy is based on “monoamine deficiency” as the underlying etiology and pathogenesis of depression. This hypothesis was formulated around 1960 and was based on the serendipitous clinical observation of an antidepressant effect associated with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Monoaminergic (serotonergic, noradrenergic, and dopaminergic) neurons are present in the midbrain and project to almost all areas of the brain, consistent with the involvement of the monoaminergic system in a broad range of brain functions, including mood, cognition, attention, appetite, sleep, and reward processing.4 Marketed antidepressants elevate synaptic levels of serotonin (5-hydroxytryptamine, 5-HT; 1) and/or norepinephrine (NE; 2) by blocking the monoamine transporters, SERT (serotonin transporter), and/or NET (norepinephrine transporter).5 However, dopamine (DA; 3), for which reuptake is mediated by the dopamine transporter © 2017 American Chemical Society

(DAT), has also been implicated in the pathophysiology of depression (Figure 1).4,6 Focusing mainly on the recent

Figure 1. Key monoamines involved in the pathophysiology of depression.

literature (2008−2016), this perspective reviews: (1) the relevance of dopamine signaling in the pathophysiology and treatment of depression in the context of the limitations of existing antidepressants, (2) the emergence of dopaminergicinclusive TRIs as potential next-generation antidepressants, their therapeutic potential in other disorders, and the possible challenges associated with their development, and (3) the rational design and discovery of different chemical series of TRIs along with their pharmacological and pharmacokinetic evaluation. Received: December 13, 2016 Published: July 21, 2017 2133

DOI: 10.1021/acs.jmedchem.6b01827 J. Med. Chem. 2018, 61, 2133−2165

Journal of Medicinal Chemistry

Perspective

Figure 2. Select examples of TCAs and MAOIs as first-generation antidepressants.

Figure 3. Monoamine transporter blockade by existing single and dual reuptake inhibitors.

Figure 4. Structures of marketed single and dual reuptake inhibitors, including first-line antidepressants (awithdrawn from the market).

2. EXISTING ANTIDEPRESSANTS AND THEIR LIMITATIONS First generation TCAs (4−8) including desipramine (4) and imipramine (5) and MAOIs including tranylcypromine (9) were introduced in the 1950s after being serendipitously discovered to be effective in treating depression (Figure 2).5

They were later shown to increase monoaminergic neurotransmission either by blocking the reuptake of monoamine neurotransmitters or by preventing their metabolism. These drugs are now largely restricted to use in severe or refractory depression due to poor tolerance. While TCAs are known to cause cardiovascular, anticholinergic and sedative side effects 2134



Perspective

Figure 5. Underlying contributors to the large unmet clinical need with first-line antidepressants.

impairment.4 Anhedonia, which is the loss of pleasure in rewarding activities, is one of the core symptoms of depression. Moreover, side effects associated with SSRIs and SNRIs, most notably sexual dysfunction and weight gain, can lead to poor adherence or treatment discontinuation among patients. Any new treatment that would demonstrate an improvement of efficacy and time to onset with the mitigation of residual symptoms and side effects would constitute a significant advance in the treatment paradigm. Hence, there is a compelling need to develop next-generation antidepressants.

due to the off-target pharmacology (for example, adrenergic, histaminergic, and muscarinic receptors), MAOIs produce dietary and drug−drug interactions that can be lethal.7 Shortcomings of TCAs led to the discovery of selective serotonin reuptake inhibitors (SSRIs; 10−15), which selectively inhibit 5-HT reuptake in serotonergic neurons (Figures 3 and 4).5 These drugs represented a major advance in the treatment of depression with an improved safety and tolerability profile. Subsequent observations of the antidepressant or other therapeutic effects of compounds that selectively block the neurotransmitter uptake in noradrenergic neurons led to the discovery of norepinephrine reuptake inhibitors (NRIs; 16,17). The combination of inhibition of reuptake in both serotonergic and noradrenergic neurons was the natural evolutionary step that led to the development of dual reuptake inhibitors, SNRIs (18−22). Second-generation agents, especially SSRIs and SNRIs, are now prescribed as the standard of care (SoC). Despite their improved safety and tolerability profile, they are not superior to TCAs and MAOIs in terms of efficacy and latency of onset.7 Bupropion (23), which belongs to a different class of dual reuptake inhibitors as a combined norepinephrine and dopamine reuptake inhibitor (NDRI), has also been approved to treat MDD.8 While 23 also acts as a releasing agent of NE and DA, its major metabolite, hydroxybupropion, is also known to be a NET inhibitor.9 Nomifensine (24) is another NDRI that was approved to treat depression but was later withdrawn due to safety reasons.10 In spite of improvements in the profiles of antidepressant medications, a large unmet clinical need still exists in terms of response rate, treatment onset, residual symptoms, and side effect profile (Figure 5). As is evident from the STAR*D clinical trial, which evaluated the effectiveness of antidepressants including switching to a different medication or medication combination, only one-third of patients recover on treatment with a single antidepressant while another onethird recover only after several months of different and multiple therapy trials.11 These drugs exhibit a clinical response as measured by a mood-elevating effect only after 2−4 weeks, although their pharmacological action occurs within a few hours of drug ingestion. As high rates of morbidity and mortality are prevalent during this latent period, it poses a critical public health problem. Another major drawback is the relapse or recurrence of depression which patients may experience following an initial short-term treatment of acute depressive episodes with antidepressants. The recurrence rate is alarmingly high, with 50% or more experiencing depression within six months of remission when an initially effective treatment with antidepressants is discontinued.12 Importantly, they are less effective in the treatment of depressive symptoms resulting from an impaired positive mood, particularly anhedonia, amotivation, loss of energy/enthusiasm, fatigue, and cognitive

3. THE ROLE OF DOPAMINE IN THE PATHOPHYSIOLOGY OF DEPRESSION 3.1. Dopaminergic System and Dysfunction. Research conducted over the past few decades has suggested that dopaminergic pathways regulate positive aspects of mood or motivational aspects of behavior.4,6 The nigrostriatal pathway, which transmits DA to the caudate nucleus and putamen from the substantia nigra, primarily regulates motor function that includes planning and execution of movement. The mesolimbic pathway, which transmits DA from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), is linked to rewardrelated, hedonic, and motivational behaviors. The mesocortical pathway, which innervates the cortex from the VTA, is believed to be important for concentration and executive functions like working memory. The functional impairment of dopaminergic pathways can cause a deficiency in the behavioral aspects of positive mood, including psychomotor speed, the ability to experience pleasure, motivation, concentration, and other behaviors, which may translate into prominent symptoms for depressed patients. The regulation of DA function through homeostatic mechanisms requires a delicate balance of synthesis, storage, release, reuptake, and metabolism of the neurotransmitter that is believed to be critical for a normal positive mood state.13 DAT plays a critical role in DA recycling by removing DA from the synaptic space, leading to the termination of DA signaling and reaccumulation in the presynaptic terminals.14 Consistent with the key role of the DA system in several aspects of brain function, an absence of DAT in mice was shown to cause changes in behavioral, physical, and pharmacological activities, including hyperactivity, sleep dysregulation, reduced weight, and pronounced reduction of hyperactivity with psychostimulants.15 All of these effects can be attributed to observed changes in the DA system including higher levels of extracellular DA, reduced levels of presynaptic DA synthesis and DA-synthesizing enzymes, and altered levels and function of DA receptors. The alteration of DAT function or density has been implicated in several CNS disorders, including depression, anxiety, attention deficit hyperactivity disorder (ADHD), and 2135



Perspective

Figure 6. Examples of psychostimulants and other agents, which involve DAT inhibition as part of their pharmacological actions.

in decreased selection of high effort/high reward choices and increased selection of low effort/low reward options.26 Tetrabenazine (43; Figure 10), which is a vesicular monoamine transporter-2 (VMAT-2) inhibitor, blocks the storage of monoamines, thereby depleting levels of these neurotransmitters, with a major impact on striatal DA.27 The DAT inhibitor PRX-14040 (34) was recently shown to reverse the effects of 43 in rats by increasing lever pressing and decreasing chow intake, with efficacy comparable to that of the dopaminergic agents 23, 25, and 32.27 Compound 23 increased the motivation to work for food reinforcement in rats, consistent with a significant increase in extracellular levels of DA in the NAc at the behaviorally active doses.28 Extinction of intracranial self-stimulation (ICSS), in which rodents self-administer a rewarding electrical stimulation, led to a significant decrease in goal-directed behaviors. This effect correlated with a significant decrease in cue-evoked phasic DA, while subsequent reinstatement restored cue-evoked DA release and re-establishment of ICSS behavior, suggesting a role for NAc DA in the reward-related pathways.29 Intraperitoneal injection of dilute acid (ip acid), a preclinical model for pain involving a chemical noxious stimulus, depressed both ICSS and extracellular DA levels in the NAc in rats (Figure 8).30 In the rat FST model, DA-potentiating agents [D2/D3 agonists and 24 (NDRI)] reduced immobility time, and this antidepressant-like effect was reduced by D2/D3 antagonists.31 Co-administration of subactive doses (ip) of the NDRI 23 along with other antidepressants, including 11, paroxetine (13), fluvoxamine (14), venlafaxine (19), and 21, at inactive doses decreased the immobility time in the mouse FST, suggesting that 23 may enhance the efficacy of SSRIs and SNRIs, consistent with preliminary clinical evidence.32 Acute administration of ketamine (35), an NMDA receptor antagonist with clinically proven and rapidly acting antidepressant properties, and LY341495 (36), an mGlu2/3 receptor antagonist, but not the SSRI 11, was shown to activate dopaminergic neurotransmission in the preclinical models (Figure 7).22 Both 35 and 36 were shown to increase the number of spontaneously active DA neurons in the VTA and increase the extracellular levels of DA in the NAc and prefrontal cortex (PFC). 3.3. Clinical Studies. 3.3.1. Introduction. Although the results from cerebrospinal fluid (CSF) analyses of depressed patients and post-mortem brain studies are not concordant, there is reasonable evidence for reduced levels of homovanillic acid (HVA), the primary metabolite of DA, as a biomarker for depression.33 Compared to healthy subjects, a lower concen-

Parkinson’s disease (PD). Psychostimulants, including cocaine (27) and amphetamine (29), drugs like methylphenidate (25), d-amphetamine (30), and lisdexamfetamine (31; a prodrug of 30) used to treat ADHD, and modafinil (32), used in the treatment of narcolepsy, elicit their behavioral effects, in part, through DAT inhibition (Figures 4 and 6).4,16 The stimulant drug 29 also competes with DA as a substrate for DAT and triggers DA release from presynaptic neurons through reverse transport by DAT.17 Though 32 is known for poor in vitro DAT activity, it has demonstrated significant DAT occupancy (≥50%) in preclinical and clinical PET studies.18,19 This compound also acts as a D2 agonist. 3.2. Preclinical Studies. Studies conducted in different rodent models of depression have indicated that the enhancement of dopaminergic neurotransmission elicits antidepressantlike effects while the suppression of this neurotransmission causes depression-like effects (Figure 8). DAT knockout (KO) mice, which are reported to experience a chronic elevation of DA, have exhibited an antidepressant-like phenotype in several behavioral models including the forced swim test (FST), the tail suspension test (TST), and the sucrose consumption test (SCT).20 Recently, inhibition of DA neuronal cells in the VTA by an optogenetic method (a technique that combines optics and genetics to control the activities of neurons in a freely moving animal and study the behavioral effect) was shown to induce depression-like phenotypes such as increased immobility time (TST) and decreased sucrose preference (SCT) in mice, thereby linking dysfunction of VTA DA neurons to depressionlike behaviors.21,22 In contrast, phasic activation of VTA DA neurons was found to reverse the depression-like behaviors in the TST and SCT models induced by chronic mild stress (CMS). Rodents showed a gradual decrease in responsiveness to rewards and in the performance of other motivated (e.g., aggressive and sexual) behaviors on exposure to CMS.23 While CMS-induced anhedonia was found to be reversible by partial DA agonists, exposure of the recovered rodents to D2/D3 antagonists resulted in a decreased reward response.6,24 Flinders sensitive line rats, a selectively bred animal model of human depression, displayed symptoms similar to those of depressed individuals, including altered sleep patterns, reduced appetite, and anhedonia. These observations are consistent with impaired DA neurotransmission that is reflected in low basal extracellular levels of DA in the limbic system, deficiency in dopaminergic tonic release in the NAc, and reduced cell activity in the VTA.25 In effort-expenditure models of depression, DA antagonism or reduced DA concentration in the NAc resulted 2136



Perspective

3.3.2. Monoamine Depletion Studies. Several clinical studies that involve an acute reduction of DA synthesis through catecholamine (NE/DA) depletion have provided support for the potential link between reduced DA levels and depression.34 Administration of α-methyl-para-tyrosine (42), an inhibitor of tyrosine hydroxylase which is involved in catecholamine biosynthesis, was shown to result in increase or relapse of depressive symptoms in remitted MDD (RMDD) subjects (Figure 10).34 RMDD subjects but not the healthy control subjects were shown to develop performance deficits on a reward processing task upon catecholamine depletion (CD).43 In RMDD subjects, tryptophan depletion (TD) caused a more depressive mood and deeper feelings of hopelessness and sadness than CD, while CD caused higher levels of inactivity, lassitude, problems with concentration, and somatic anxiety than TD. This suggests both common and differential roles of 5-HT and catecholamines (NE/DA) in the pathophysiology of depression.44 Compound 43, which is a monoamine-depleting agent and an approved medicine for the treatment of Huntington’s disease, is known to induce depression as a major side effect.27 Reserpine (44), another monoaminedepleting agent, has been reported to induce clinical depression, although this has been questioned.45 3.3.3. Efficacy with DA Enhancers. Different types of drugs including MAOIs, atypical TCAs (e.g., amineptine [8]), NDRIs (23 and 24), dopamine receptor agonists, and psychostimulants, all of which appear to elevate DA neurotransmission, have been suggested to be effective in the treatment of MDD (Figures 2, 4, 6, and 11).4 Several clinical trials have indicated an antidepressant response to treatment with MAOIs in depressed and treatment-resistant subjects.46,47 The DATselective TCA 8 was shown to be an effective therapy for depressed patients with anhedonic, apathetic, socially withdrawn, psychomotor-retarded, and melancholic features.4 The NDRI 23 is the preferred treatment for MDD patients who cannot tolerate SSRIs and/or SNRIs. A meta-analysis of comparator clinical trials supported evidence for the equivalent efficacy of 23 to SSRIs and SNRIs.8 It is frequently used as an adjunct drug with SSRIs and SNRIs in order to enhance efficacy or reduce side effects. Augmentation of the SSRI 11 with 23 showed a greater reduction in depressive symptoms with fewer side effects.8 Compared to SSRIs, 23 was shown to improve the resolution of fatigue and sleepiness in RMDD patients, consistent with its pharmacology.48 Psychostimulants that are known to act on the DAT were shown to activate the reward system, reduce fatigue and apathy, and promote alertness and wakefulness, thereby contributing to antidepressant efficacy, especially when used as adjunctive agents.4 The wakefulness-promoting agent 32 was shown to

Figure 7. Agents that indirectly activate dopaminergic mood circuits through NMDA or mGlu2/3 receptor antagonism.

tration of HVA was found in CSF, the internal jugular vein, and the plasma of depressed patients, especially those with TRD or melancholic depression.34 DA is associated with appetitive behaviors, and this may underlie the observation that MDD patients appear to possess reward processing dysfunction, manifested as, fatigue, loss of energy, and reduced exertion of effort.26,35 MDD patients showed a reduced willingness to exert physical effort to secure bigger rewards. A dose-dependent increase in the willingness to work for rewards was observed upon oral dosing of 30 in the effort expenditure for rewards task.36 Striatal DA deficiency is a prominent feature in the pathophysiology of PD, a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons.37 Depression occurs with high prevalence (∼35%) in PD patients with anhedonia as a key symptom, an observation that supports the association of depression with dopaminergic dysfunction. Neuroimaging studies have indicated the prevalence of altered dopaminergic states (alteration in DA synthesis and expression of DA receptors and DAT) in depression, although conflicting results were obtained possibly due to the heterogeneity of the disorder.38 In the amygdala of postmortem brain samples of MDD patients, reduced DAT levels and a higher percentage of D2/D3 receptors were found.33 MDD patients with anhedonic symptoms showed decreased DAT binding.39 Decreased striatal DAT binding was observed in MDD patients using the DAT-selective PET tracer [11C]altropane (37).40 Uptake of the SPECT ligand 99mTcTRODAT-1 (38) was significantly reduced in the striatum compared to the cerebellum in MDD subjects (Figure 9).41 Studies in humans and animals have provided consistent evidence that inflammatory cytokines affect DA levels in the basal ganglia to induce depressive symptoms.42 Results from these studies, which included inflammation-mediated decreases in ventral striatal response to hedonic reward, reduced levels of DA and its metabolites in CSF, and reduced availability of striatal DA, correlated well with the depressive symptoms of anhedonia, fatigue, and psychomotor retardation.

Figure 8. Inducement of depression-like or antidepressant-like effects based upon the potential alteration of dopaminergic neurotransmission in rodents (aintracranial self-stimulation). 2137



Perspective

Figure 9. Structures of DAT-binding PET and SPECT tracers.

Figure 10. Agents that cause the depletion of monoamines, including DA, by blocking their synthesis or storage.

Figure 11. Examples of dopamine agonists and atypical antipsychotics, known to demonstrate the clinical antidepressant effect.

Figure 12. Clinical observations potentially related to impaired dopaminergic neurotransmission in affective disorder (aRMDD, remitted MDD; b dopamine reuptake inhibitors (DRIs), DA agonists, psychostimulants, and MAOIs).

found to show antidepressant effects in several small clinical trials for the treatment of MDD and TRD (Figure 11).4,49 The DA agonist 47, which is approved for treating PD and restless leg syndrome, was found to be efficacious in refractory unipolar depression and refractory bipolar depression as an augmenta-

improve depression scores and remission rates as an augmentation agent, with positive effects on fatigue symptoms.16 DA receptor agonists, including ergot alkaloids (e.g., bromocriptine [45] and pergolide [46]) and nonergot agonists (for example, pramipexole [47] and ropinirole [48]) were 2138



Perspective

Figure 13. Hypothesis that augmentation of 5-HT and NE with DA will lead to an enhanced antidepressant effect as the result of synergistic effects while minimizing side effects through an antagonist action.

tion agent for use with SSRIs.50 A recent meta-analysis of randomized clinical trials provided evidence that atypical antipsychotics significantly improved the response and remission rates when used as adjunctive therapies in TRD.51 Aripiprazole (49), which is an atypical antipsychotic, appears to derive a therapeutic effect, in part, by alteration of the dopaminergic system (e.g., D2/D3 partial agonism).52 Selected clinical observations that are potentially related to impaired dopaminergic neurotransmission in affective disorder are summarized in Figure 12.

premature ejaculation, in contrast, TRIs are expected to normalize sexual dysfunction due to the opposing effects of 5-HT and DA. The NDRI 23 is frequently used as an adjunctive therapy to reduce the sexual dysfunction associated with SSRI treatment. Considering the factors discussed above, there appears to exist a sufficient rationale to seek a single antidepressant drug which can simultaneously enhance all three biogenic amines, thereby mitigating the limitations of single and dual reuptake inhibitors (Figure 13). In view of the diversity of depressive symptoms and considering affective disorder as a multifactorial syndrome, TRIs, which modulate three monoaminergic pathways, constitute a potential strategy for enhancing antidepressant efficacy because all of these pathways are interrelated. Although a functional TRI regimen can be achieved by combining drugs, for example, an SNRI + a DRI or a SSRI + an NDRI, this may lead to confounding pharmacokinetic and compliance issues. TRI monotherapy could reduce the requirement for combinations of multiple antidepressants, for which there is a lack of efficacy data, poor compliance due to complex dosing regimens, the risk of drug−drug interactions, and the possibility of cumulative toxicity.54 MAOIs, which increase all three monoamines by preventing amine metabolism, represent an alternative triple acting approach that may strengthen the case for TRIs (Figure 14).46,47 The reversible

4. TRIs/SEROTONIN NOREPINEPHRINE DOPAMINE REUPTAKE INHIBITORS (SNDRIs) 4.1. Therapeutic Potential As Broad-Spectrum Antidepressants. Burgeoning evidence from both preclinical and clinical studies, as summarized in the preceding section, implicates the dysfunction of dopaminergic neurotransmission in the etiology of major depression. The prevalence or inducement of DA hypofunction has been shown to manifest as symptoms of depression. On the other hand, correction of DA dysfunction by therapeutic agents that act by DA potentiation through different mechanisms and those that modulate postsynaptic dopamine receptors directly or indirectly has been shown to result in antidepressant effects in various animal models and in clinical trials. While SSRIs and SNRIs lack a significant level of direct pharmacological action (e.g., DAT inhibition) to enhance DA neurotransmission, treatment with these drugs could even lead to inhibition or reduction of DA release through indirect receptor pharmacology including, for example, a reduction of the mean firing rate of VTA DA neurons by the SSRI 11 through 5-HT2C activation.53 This may partly account for the suboptimal response to SSRIs and the persistence of SSRI-resistant symptoms in some depressed patients. Augmentation of SSRIs and SNRIs with 23 or atypical antipsychotics has been shown to improve the response rate and/or reduce the side effects of SSRIs/SNRIs. While the improvement in the response rate can potentially be attributed to the added effect on dopaminergic neurotransmission which alleviates depressive symptoms (especially symptoms refractory to treatment with SSRIs and SNRIs), the reduced side effect profile is likely due to the counteracting effect of DA neurotransmission on the side effect pharmacology that arises from a chronic inhibition of SERT (Figure 13). For example, hyperprolactinemia, which causes impotence, is less likely to occur because DA opposes the 5-HT-promoted release of prolactin, thereby normalizing sexual function.7 While SSRIs are often prescribed to treat

Figure 14. Examples of MAO inhibitors as antidepressants that represent an alternative triple approach involving all three biogenic amines.

MAO-A inhibitor moclobemide (50) was shown to demonstrate antidepressant efficacy with lower sexual side effects than SSRIs.47 The irreversible MAO-B inhibitor selegiline (51) has been approved for the treatment MDD and is administered as a transdermal patch.46 4.2. Therapeutic Potential in Other Indications. TRIs may have therapeutic potential beyond depression when considering the implications of monoamine deficiency in various disorders that involve the central nervous system (CNS). Selective SSRIs and NRIs and dual SNRIs and NDRIs have been approved for a number of indications including anxiety, pain, substance abuse, ADHD, and appetite-related 2139



Perspective

NET-selective TCA nortriptyline (7), and the SNRI milnacipran (21) blocked acid-stimulated writhing but failed to block acid-induced depression of ICSS.63 However, the DRI RTI-113 (28) attenuated both acid-induced writhing and depression of ICSS in rats, reflecting a reversal of painstimulated and pain-depressed behavior, which suggested DRIs to be potential analgesics.63 Nefopam (52), which is a marketed non-narcotic analgesic drug, is believed to exert its effect through TRI pharmacology (Figure 15).61 The TRI bicifadine

disorders, and this supports the implication of monoamines in these disorders (Table 1).55 Dopaminergic abnormalities are Table 1. List of Disorders for Which Single and Dual Reuptake Inhibitors Are Approved, and Disorders for Which TRIs Have Been Investigated55,75 disorder generalized anxiety disorderb social anxiety disorderb panic disorderb obsessive-compulsive disorderb post-traumatic stress disorderb neuropathic painc chronic musculoskeletal painc fibromyalgiac stimulant addiction (e. g., cocaine)d AUDd tobacco addiction (nicotine dependence)d obesitye bulimia nervosae binge eating disorder (BED)e ADHD PD urinary stress continence premenstrual dysphoric disorder type 2 diabetes a

marketed reuptake inhibitorsa

investigational TRI

SSRI, SNRI SSRI SSRI, SNRI, NRI SSRI SSRI, SNRI SNRI SNRI, NDRI SNRI

58,61 61,30 and 7262

6465

NDRI SNRI, NDRI SSRI NRI, NDRI

Figure 15. Structure of 52, a marketed analgesic drug that is known be a TRI.

6067 and 6167 6166

(58) has shown antinociceptive effects in several preclinical models of pain and select types of clinical pain.61,64 Amitifadine/DOV 21,947 (61), an analogue of 58, was recently shown to reverse IP-acid induced depression of NAc DA, ICSS and stretching in rats (ip), supporting 61 as a potential analgesic to treat pain-related depression.30 4.2.3. Substance Dependence Disorders. TRIs have been investigated for treatment of cocaine addiction, nicotine addiction, and alcohol use disorder (AUD). The TRI 64 is being investigated for the treatment of cocaine addiction.65 In a phase 1 human laboratory interaction study, 64 reduced the rewarding valence of a 20 or 40 mg dose of cocaine. The NDRI 23 has been approved for smoking cessation in addition to depression. The TRI 61 significantly decreased the amount of nicotine self-administration in rats at a dose of 30 mpk (po).66 The significant reduction of self-administration did not diminish over 2 weeks of chronic treatment at a dose of 10 mpk and a week after enforced abstinence. This suggests that 61 may be useful for smoking cessation. DOV 102,677 (60) and 61 have been investigated for treating AUD. In high alcohol-preferring mice (a rodent model for studying the relationship between excessive alcohol drinking and impulsivity), 60 and 61 attenuated binge drinking, heavy drinking (24 h free choice assay), and impulsivity (delay discounting method).67 This suggested that these inhibitors might be useful to treat alcoholism with co-occurring excessive drinking and impulsivity. 4.2.4. Metabolic and Eating Disorders. Several studies have indicated the important role of the dopaminergic system in the regulation of food consumption and the contribution of DA dysregulation to the development of obesity.68 Activation of DA neurotransmission is believed to suppress feeding activity and produce anorectic effects. A combination of 23 and the opioid receptor antagonist naltrexone (53) was recently approved for the treatment of obesity.9 The TRIs 61 and tesofensine (63) have shown weight reducing effects in clinical trials, suggesting the potential use of TRIs to treat obesity or depression that is comorbid with obesity.69,70 The weight reducing effects of 63 were significantly greater than that of any current antiobesity drugs and appear to be due to a pronounced decrease in appetite coupled with a slight contribution from

6169 and 6376 6574 62,58 64,59 and 6560 6377

SNRI SSRI 63f,71 b

Single or dual reuptake inhibitors. A type of anxiety disorder. cA type of pain disorder. dA type of substance dependence. eAn appetiterelated disorder. fAs Tesomet in combination with 54

implicated in a number of disease states including pain, addiction, appetite, ADHD, PD, and schizophrenia, and some of these CNS disorders are frequently comorbid with depression. TRIs may be useful to treat many of these indications, especially, those that involve the hypofunction of all three monoamines. 4.2.1. ADHD. Although the precise etiology of ADHD is yet to be understood, several lines of evidence support the implication of catecholaminergic functional deficit in ADHD, which is consistent with the use of the NDRI 25 as the SoC for ADHD.56 In an animal model of ADHD, centanafadine (62) produced dose-dependent inhibition of locomotor hyperactivity in juvenile rats (ip) lesioned with the neurotoxin 6-hydroxydopamine.57 Three TRIs, 62, NS2359 (64), and dasotraline (65), have been investigated in the clinical trials for the treatment of ADHD, while 62 and 65 have demonstrated statistically significant efficacy in small trials (Figure 18).58−60 4.2.2. Pain. About 75% of MDD patients suffer from painful symptoms, suggesting a high comorbidity and common neuronal pathways between pain and depression.61 DA is known to be involved in the regulation of pain, particularly analgesia.62 L-DOPA and 23, which enhance DA neurotransmission, have produced analgesic effects in several models of neuropathic pain. Increasing evidence suggests that dopaminergic dysfunction may contribute to depressive effects of pain.30 Acid-induced depression of ICSS was found to be blocked by DRIs but exacerbated by DA receptor antagonists. The SSRI citalopram (11), the TCA clomipramine (6), the 2140



Perspective

both in animals and in humans and, importantly, a PET study allows the in vivo estimation of the relationship between exposure and target occupancy. Second, a microdialysis experiment is associated with ambiguities because 5-HT, NE, and DA are elevated to different levels in different brain regions. Typically, SERT occupancy is at least 80% at clinically efficacious doses following chronic treatment with SSRIs.54 NET occupancy of 7, an NET-selective TCA, was shown to be 50−70% at the efficacious doses based on PET studies conducted in MDD patients.81 In contrast, a therapeutic effect is usually achieved with DAT occupancy of ∼30%, as evident from PET studies of 23 at the therapeutically effective dose.54 Taking all of these factors into consideration, it seems appropriate to develop a TRI with SERT, NET, and DAT occupancies of ≥80%, 50−70%, and ≤30%, respectively, based on the concept that antidepressant efficacy with reduced NET and DAT inhibition will minimize adverse effects (Table 2). As discussed earlier, drugs which extensively inhibit DAT are associated with stimulant effects and abuse, as exemplified by 27. Because 27 is also a TRI, this would pose a serious concern with respect to the development of any TRI which will require a clinically demonstrated low potential for addictive liability because this would otherwise restrict its utility as a controlled substance. However, DAT inhibitors have successfully been developed into drugs with manageable abuse liability, as exemplified by 23, 25, and dexmethylphenidate (26). The addictive liability of stimulants, which appears to be correlated with the magnitude and rate of enhancement of intrasynaptic DA release in the mesocorticolimbic region, is closely linked to the degree and rate of DAT occupancy, brain clearance rate, and half-life of the stimulants (Figure 19).83 In human PET studies, 23 and 25 exhibit DAT

triple occupancy (in vivo) hERG inhibition

≥80%/50−70%/≤30% (SERT/NET/DAT)

CYP2D6 inhibition mitigate abuse potential

desired profile

triple affinity (in vitro)a

brain uptake brain clearance

in vitro IC50 > 10 μMa (in vivob: ≥30-fold hERG IC50/free Cmax)82 in vitro IC50 > 10 μMa (in vivob: NET > DAT, a profile that reflects consideration of the side effects associated with profound inhibition of NET and DAT. In this section, relevant journal articles but not patent applications (with a few exceptions) are summarized in deference to space constraints and the recent appearance of a review of the patent literature associated with TRIs.92 5.1. DOV Series. Compounds based on a 3azabicyclo[3.1.0]hexane template were disclosed by American Cyanamid as analgesic agents in the late 1970s, with the subsequent disclosure of antidepressant properties several years later.97,98 DOV Pharmaceuticals progressed some of these

transporters. In some instances, the TRI programs appeared to be an extension of previous programs seeking single or dual reuptake inhibitors that allowed taking advantage of internal leads as starting points. In a few cases, existing TRIs, including 27, 61, and trans-sertraline (73), were exploited for further optimization to generate novel compounds with diverse ratios of triple transporter affinity (Figures 21, 22, 24, 25, and 28, 29). The key pharmacophoric features of a typical TRI consist of a positively charged moiety, two or three hydrophobic regions inclusive of an aromatic group and a putative hydrogen-bond acceptor zone (Figure 20).90,91 The fundamental requirement

Figure 20. A representative TRI pharmacophore, reproduced from the literature.91

Figure 21. Exploration of the 3-azabicyclo[3.1.0]hexane chemotype to derive clinical TRIs (DOV). 2143



Perspective

Figure 22. Design of tropane-bearing TRIs by modifying the ester functionalities of 27 leading to the identification of two clinical candidates (Neurosearch/Saniona).

volitional consumption of ethanol with minimal alterations to food intake or body weight (20 mpk, ip).103 In another study, 60 produced a prolonged and selective reduction of alcoholmotivated responses with a robust antidepressant-like effect and no significant alteration of sucrose consumption in alcoholpreferring rats (po), suggesting that 60 may be useful to treat comorbid AUD and depression.104 Although 60 entered a phase I clinical trial to treat alcohol abuse and alcoholism in 2006, no recent development activity has been reported.75 Compound 61, which is the (+)-enantiomer of 59, is being developed by Euthymics Bioscience for AUD and smoking cessation (Figure 21).94 Compound 61 showed ex vivo occupancy ED50 values of 0.5, 2, and 49 mpk (ip) for SERT, NET, and DAT, respectively, in rats.89 Compound 61 exhibited high human plasma protein binding, high permeability, metabolism by MAO-A in human hepatocytes, weak inhibition of metabolizing enzymes, and a good brain-to-plasma (B/P) ratio in rats.105 Compound 61 showed a dose-dependent reduction in immobility time in both the rat FST and mouse TST models at doses of 5, 10, and 20 mpk po and did not induce locomotor activity at the active doses.106 Compound 61 demonstrated dose-dependent reduction of binge alcohol drinking but not binge sucrose drinking.107 It reversed two measures of negative impact of abstinence (immobility and increase in ICSS threshold), which suggested that 61 might be effective in treating comorbid alcoholism and depression. Compound 61 demonstrated a significant reduction in body weight and plasma triglycerides in diet-induced obesity (DIO) mice and rats (po) with a transient decrease in food consumption but a sustained decrease in fat mass.108 It also produced a sustained reduction in the rate of weight gain for up to 1 year in normal dogs and did not significantly affect blood pressure, heart rate, or ECG parameters in dog telemetry studies. Hence, 61 may be effective for the treatment of obesity or depression comorbid with obesity. In an eight-week, doubleblind and placebo-controlled phase I study, 61 at doses of 50, 100, and 150 mg, qid produced statistically significant reductions in both body weight and plasma triglyceride levels.69 Compound 61 was safe and well tolerated at the dose range studied with no serious adverse events observed. In a 6-week, randomized, double-blind and placebo-controlled study of 63 patients with MDD administered with a dose of 25 mg (b.i.d.) for 2 weeks and 50 mg (b.i.d.) for the following 4 weeks, 61 showed significant efficacy at attenuating anhedonic symptoms.109 However, in a subsequent study of 342 MDD patients with TRD where 13 was used as the active control drug, no significant separation from placebo was observed at doses of 50 and 100 mg/day.110 Compound 62, which is a NET-preferring TRI (Figure 21), is being developed by Neurovance as a potential nonstimulant drug for the treatment of ADHD.58 In a microdialysis study, 62

earliest TRIs for the treatment of depression and other indications (Figure 21). In the DOV series, 58 was the first compound to reach clinical development as an analgesic drug candidate.61,64 In a microdialysis experiment, 58 increased extracellular levels of 5-HT, NE, and DA in brain regions in rats following oral administration of doses associated with analgesia. Compound 58 attenuated pain responses in models of acute inflammatory pain conducted in rats and mice, normalized the nociceptive threshold in a model of persistent inflammatory pain, and suppressed thermal and mechanical hyperalgesia and mechanical allodynia in the spinal nerve ligation model of chronic neuropathic pain. In phase II trials, 58 has shown clinical efficacy in the treatment of acute dental and postbunionectomy pain but failed to show efficacy for chronic lower back pain or diabetic neuropathic pain.61,64,75 Modification of the aryl group in 58 led to the identification of the additional clinical candidates 59−62 (Figure 21). Compound 59, studied as a racemic mixture, showed ex vivo binding affinity in the order of SERT > NET > DAT (ED50: 3, 19, and 95 mpk for SERT, NET, and DAT occupancy, respectively) in rats.89,99 A reduction in immobility was observed at an oral dose of 10 mpk in the mouse FST model. Following oral administration to mice, 59 reversed both motor depression (MED: 1.6 mpk) and ptosis (ED50: 2.2 mpk) induced by 43. In rats (po), 59 was shown to induce an enhancement of brain reward activity (potential to treat anhedonia), as evident from a decreased ICSS threshold.100 In the differential reinforcement of low rate 72 s responding assay (a behavioral model that is predictive of antidepressantlike activity), 59 significantly increased the reinforcement rate at one intermediate dose but showed comparable effects to the dopaminergic agents 23 and GBR12909 (33) on inter-response time distribution in rats (ip).101 This result suggested a limited antidepressant-like effect of 59. Following single oral doses to rats and dogs, 59 showed dose-proportional exposure and was well-tolerated at doses below 100 mpk. In a double-blind phase II randomized clinical trial of 67 subjects with moderate to severe MDD, 59 demonstrated a significant (>40%) reduction in the total HAM-D scores, although the study lacked a placebo control arm.75,99 Its efficacy at 50 mg, b.i.d. was found to be comparable to that of the active control 11 administered at a dose of 20 mg, b.i.d. without any serious adverse events. However, further development of 59 was discontinued for IP reasons.93 Compound 60 is the (−)-enantiomer of 59 (Figure 21).102 Compound 60 markedly increased the extracellular levels of 5HT, DA, and NE in the PFC and of DA and 5-HT in the NAc at a dose of 20 mpk ip in rats. In the rat FST model, 60 exhibited an antidepressant-like activity with an MED of 20 mpk po and maximal efficacy comparable to that of 5. In an ethanol-preferring rat strain, 60 significantly reduced the 2144



Perspective

Figure 23. Diastereomeric switch of the SSRI 15 to enhance NET/DAT activity leading to the identification of 65 as a clinical candidate (Sepracor/ Sunovion); aaffinity data are taken from the literature.117

SPECT imaging study conducted in healthy subjects, an 0.5 mg dose of 64 was shown to afford DA occupancy of 35%, which was in the range of other clinically effective compounds used in the treatment of ADHD. In healthy volunteers, a PET imaging study indicated SERT/DAT occupancies of 55/60% and 75/ 80% at doses of 1 and 2 mg, respectively.114 Compound 64 is being developed by Saniona AB for the treatment of cocaine addiction.65 Further SAR exploration with a chromene ring as an aryl replacement and elimination of the alkoxylalkyl side chain gave a new series of tropane derivatives that included NS18283 (72).115 Hache et al. have reported the antinociceptive activity of 72 in a mouse model of chemotherapy-induced neuropathic pain (Figure 22).62 This compound significantly increased extracellular concentrations of 5-HT, NE, and DA in the anterior cingulate cortex of oxaliplatin-treated mice experiencing neuropathic pain at a dose of 10 mpk (sc). In contrast, escitalopram (12) increased only 5-HT levels and the SNRI 19 increased only 5-HT and NE concentrations. Compound 72 reversed oxaliplatin-induced mechanical hypersensitivity and cold allodynia but failed to reverse cold hyperalgesia. The compound exhibited antidepressant-like activity in the anxiousdepressive phenotype of oxaliplatin-treated mice in TST. 5.3. Sepracor (SEP)/Sunovion Series. Compound 65, which was earlier investigated for treating MDD, is being developed for ADHD and BED by Sunovion Inc. (Figure 23).60 Compounds 65 and 73, which were synthesized and evaluated for triple reuptake inhibition as part of SAR development around cis-sertraline (15) in the late 1980s by Pfizer, received attention recently because of the renewed interest in TRIs.116 Compound 65 demonstrated a significant reduction of immobility in the mouse FST model at doses of 10 and 30 mpk ip with higher efficacy than 5. However, 65 did not meet the primary end point in a phase II clinical trial of 514 patients with MDD even though the positive control arm (venlafaxine XR) achieved a statistically significant separation from placebo.75 The systemic exposure of 65 was much lower than expected at the doses tested (0.5 and 2.0 mg) relative to the exposure profiles from several phase I clinical trials. A subsequent PET study with healthy subjects indicated SERT and DAT occupancies to be 2−14% and 33−49%, respectively, over the dose range of 8−16 mg, which was at least 4-fold higher than the highest phase II clinical dose.79 In an ADHD population (phase I/II, 4−8 mg), 65 showed a long half-life (t1/2: 47 h) with steady state plasma concentrations reached after 10 days. In a randomized, double-blind and placebocontrolled PoC clinical study, 65 demonstrated an improvement in the symptoms of ADHD at a dose of 4 mg/day that was statistically significant at a dose of 8 mg/day.56 In a phase 2/3 clinical trial for BED, 65 demonstrated statistically significant efficacy at a dose of 4−8 mg/day.75

increased NE and DA concentrations in the PFC by 375% and 300%, respectively, at a dose of 20 mpk (ip) in rats.57 Compound 62 dose-dependently reduced immobility in the mouse TST (po) and did not stimulate locomotor activity in the efficacious dose range of 3−10 mpk in rats. In a phase 2b clinical trial, 62 met both primary and secondary end points in the treatment of adult ADHD.58 The 400 mg/day dose evaluated in this study was well-tolerated with lower rates of insomnia and loss of appetite compared to stimulants. 5.2. Neurosearch (NS) Series. Neurosearch have reported a series of tropane derivatives derived by modifying the naturally occurring TRI 27 with a focus on improving both the triple reuptake inhibition profile and in vivo stability, an initiative that resulted in the identification of at least two clinical candidates (Figure 22). Compound 63 is being developed by Saniona AB as a monotherapy for the treatment of obesity and as a combination therapy with 54 for the treatment of type 2 diabetes.71,95 Compound 63 was originally developed for the treatment of Alzheimer’s or Parkinson’s disease but did not exhibit an adequate efficacy in early clinical trials.70,77,111 However, significant weight loss was observed in subjects who were classified as obese. In a subsequent clinical trial, 63 induced reductions in body weight of 4.5%, 9.2%, and 10.6% at the respective doses of 0.25, 0.5, and 1.0 mg/day administered for a period of 6 months.112 However, 63 caused an increase in heart rate and blood pressure at the therapeutically relevant doses. A fixed dose combination of 63 and the antihypertensive agent 54 prevented the cardiovascular sympathetic effects of 63 without affecting the inhibitory effect on food intake in rats.113 In DIO rats, 63 produced a significant and dose-dependent weight loss following oral administration for 28 days.76 In a PET study using [11C]βCIT-FE (40), 63 induced a dose-dependent blockade of DAT, with occupancy determined to be between 18 and 77%, following oral doses ranging from 0.125 to 1 mg, suggesting that the dose-dependent weight loss in the clinical trials was, in part, mediated by upregulation of DA neurotransmission through DAT blockade.68 Compound 64 has been investigated for the treatment of MDD and ADHD (Figure 22). In two randomized, doubleblind, placebo- and active-controlled studies (study 1, MDD patients; study 2, MDD patients with anhedonic symptoms), 64 failed to show significant efficacy (1−2 mg/day), although the active controls 13 (at 20−30 mg/day) and 19 (at 150−225 mg/day) showed statistically significant efficacy when compared to placebo.114 Compound 64 was not well-tolerated, with the observation of psychiatric (insomnia and anxiety), gastrointestinal (dry mouth), and cardiovascular (increase in heart rate and blood pressure) side effects. In a multicenter, doubleblind, randomized, and placebo-controlled phase II trial, 64 was well-tolerated at a dose of 0.5 mg/day, but the dose was not associated with an improvement in symptoms of ADHD.59 In a 2145



Perspective

Figure 24. Expanding on 73 as a starting point to probe SAR with respect to regiomerism, chirality, amino substitution, and homologation (Sepracor/Sunovion).

Figure 25. Homologation of 3-azabicyclo[3.1.0]hexane leading to the identification of 3-aryloctahydrocyclopenta[c]pyrrole and 3-aryl-octahydro1H-isoindole derivatives (Sunovion).

exemplified by the homologous compounds 87, 89, 91, and 93, with the exception of the NET potency associated with 91. Primary and secondary amines that were evaluated for in vitro ADME properties showed good human and mouse microsomal stability with the majority exhibiting t1/2 values of >300 min. The compounds showed moderate to potent CYP2D6 inhibition with nanomolar potency for compounds bearing the (S)-3,4-dichlorophenyl stereochemistry. The profiled compounds showed hERG IC50 values of ≥1.5 μM. Compound 82, which exhibited the best ADME profile in terms of microsomal stability and inhibition of CYP isoforms and hERG, was profiled in vivo. It showed a significant and dose-dependent reduction in immobility time in the mouse TST model at doses of 10−30 mpk po, a good B/P ratio (40), and a high brain concentration (44 μM). The observed efficacy was not due to locomotor activation because 82 did not increase spontaneous locomotor activity. Shao et al. reported the synthesis and pharmacological evaluation of bicyclic 3-aryloctahydrocyclopenta[c]pyrrole and 3-aryl-octahydro-1H-isoindole derivatives which followed a

Recently, 73 was exploited as the starting point to derive regioisomers by relocating the amino group on the saturated ring and homologating the spacer between the bicyclic ring and the amino group by inserting a CH2 or CH2CH2 linker (Figure 24).117 The (S)-stereochemistry at the chiral center bearing 3,4dichlorophenyl substitution imparted significantly higher SERT inhibition than the (R)-chirality. Relocation of the 1-amino group in 73 to the 2-position was tolerated, with 76 showing improved SERT potency. Further relocation to the 3-position, compound 74, was tolerated at SERT/DAT but poorly tolerated at NET. Within all of the stereoisomers 75−86, SERT potency increased in the order of NMe2 ≥ NHMe > NH2, while NHMe showed higher potency for NET/DAT than either NMe2 or NH2 groups. In addition, the trans-isomers 75 and 76 with the (2R,4S)-configuration showed higher triple reuptake inhibitory potency than the remaining three stereoisomer pairs 78 and 79, 81 and 82, and 84 and 85 when the amine was NHMe or NH2. The introduction of a methylene spacer in the primary amines 75, 78, 81, and 84 facilitated an improvement in triple reuptake inhibitory potency as 2146



Perspective

Figure 26. Psychostimulant 29 as the starting point to design 1-arylcyclohexylmethylamine chemotype (Sunovion).

Figure 27. Lead optimization of 1-arylcyclohexylmethylamine series resulting in the identification of NET-preferring 66 as a clinical candidate (Sepracor/Sunovion).

and 105 but with a significant amount of N-desmethyl metabolites detected in brain tissue. Shao et al. disclosed the triple reuptake inhibitory activity and metabolic stability profiles around the amphetaminederived chemotype, 1-aryl-1-aminomethylcyclohexane (Figure 26).119 Although the N,N-dimethyl compounds in the initial set gave the best activity, they suffered from rapid metabolism in vitro and in vivo to afford the N-monomethyl metabolites 107 and 108. To circumvent this, α-alkyl substitution proximal to the amine was investigated as a steric shielding strategy. Scanning of aryl and α-alkyl groups (as racemates) indicated that 3,4-dichlorophenyl and 2-naphthyl were the preferred aryl components while a methyl group was the preferred α-alkyl substituent. The individual enantiomers were subsequently separated and profiled. With only a few exceptions, triple reuptake affinity increased in the order of NMe2 > NHMe > NH2, while the reverse was found to be true in terms of metabolic stability. Representative compounds 110, 111, and 114 showed weak hERG (IC50: ≥4.3 μM) and CYP inhibition (CYP2D6 IC50, >5 μM; other isoforms IC50 values, >25 μM). All three compounds showed a dose-dependent reduction in immobility time in the mouse TST model over the dose range studied, 3−30 mpk po. At efficacious doses, the brain levels were significantly higher than the IC50 for the transporters, and the compounds did not alter spontaneous locomotor activity in mice. The scope of this study (vide supra) was expanded by an investigation of substitution on the cyclohexyl ring which led to the identification of the clinical compound 66 (Figure 27).120 While the prototype 115 showed poor triple reuptake inhibitory activity, inversion of the tertiary carbinol moiety

design principle of expanding the cyclopropyl ring of the 3azabicyclo[3.1.0]hexane chemotype (Figure 25).118 In the case of the octahydrocyclopenta[c]pyrrole series with N-Me substitution, aryl variation indicated that the 3,4-dichlorophenyl substitution pattern in 101 and 102 and the 2-naphthyl element in 103 and 104 were the preferred aromatic substitutions on the bicyclic ring. In the case of the octahydro-1H-isoindole series, a two-dimensional variation of N-alkyl (alkyl: Me, Et) and aryl (phenyl, substituted phenyl, and 1- or 2-naphthyl) was undertaken, which resulted in the identification of 105 with the most potential for triple reuptake inhibition. The transoctahydro-1H-isoindole compounds 99 and 100 showed lower triple potency than their cis-counterparts 97 and 98, suggesting that a cis-ring fusion was critical for potent inhibition. The general trend of superior potency at SERT of tertiary amines compared to secondary amines was maintained throughout (e.g., 101 vs 95 and 105 vs 97). In terms of microsomal stability, a secondary amine was favored over a tertiary amine and the 3,4-dichlorophenyl over the 2-naphthyl group. On the basis of potency and ADMET considerations, 95, 101, and 105 were profiled for properties in vivo. Compound 95 was a standout from the ADME perspective with excellent HLM stability (t1/2: 262 min) and moderate CYP (>5 μM) and hERG (5.28 μM) inhibition. In the mouse TST, 95 showed statistically significant efficacy following po doses of 10 and 30 mpk with the observation of a high B/P ratio (30) and a free drug concentration of ∼2 μM in the brain at 30 mpk in the test animals. It did not significantly increase spontaneous locomotor activity at the efficacious doses in mice, suggesting that the efficacy was not due to motor stimulation. A similar efficacy profile was observed with the N-methyl analogues 101 2147



Perspective

Figure 28. Exploration of peripheral substitution on the 3-azabicyclo[3.1.0]hexane chemotype to improve affinity (GSK).

Figure 29. Identification of 67 as a clinical candidate through sequential ring homologation of the 3-azabicyclo[3.1.0]hexane chemotype and appendage of a side chain (GSK).

gave 116 with improved activity while subsequent Nmethylation gave 117 and 66, which are associated with further enhanced activity. Replacing the dichlorophenyl of 66 with a 2naphthyl group gave 118, a change in structure that resulted in higher SERT activity but reduced DAT potency. Recently, an exploratory biomarker study of 66 conducted at an MTD of 300 mg/day in healthy volunteers, with duloxetine (18) as the active control at a dose of 60 mg/day, was reported.80 On day 14, 66 showed a tmax of 4 h and t1/2 of 18 h in CSF with a B/P ratio of 0.22, while the metabolite 117 showed a tmax of 6 h and a t1/2 of 32 h with a B/P ratio of 0.46. In CSF, both 66 and 18 increased NE and significantly reduced dihydroxyphenylglycol (DHPG), a metabolite of NE and biomarker for NET inhibition, relative to placebo, confirming NET inhibition. Treatment with 66 did not significantly increase CSF 5-HT levels and failed to reduce 5-hydroxyindoleacetic acid (5-HIAA) concentrations. However, 18 displayed a statistically significant increase in CSF 5-HT levels and moderately reduced 5-HIAA levels while not altering the levels of DA metabolites in either the CSF or plasma. These results suggest that clinically meaningful SERT and DAT inhibition by 66 is unlikely. The failure to translate the in vitro data to humans may be attributed to suboptimal CNS distribution, consistent with the 10-fold lower Cmax in CSF than in plasma. In a SPECT imaging study, SERT and DAT occupancies were found to be 31% and 25%, respectively. Overall, the biomarker and occupancy data suggest that 66 may not be efficacious at the MTD. 5.4. The GlaxoSmithKline (GSK) Series. Micheli et al. investigated the introduction of a side chain to the 3azabicyclo[3.1.0]hexane chemotype to potentially increase interactions with target proteins, a design based on the inhouse TRI pharmacophore model (Figure 20) that was

developed by exploiting the structures of both selective and nonselective reuptake inhibitors.90 This led to the discovery of a new series of compounds based on a 1-(aryl)-6-[alkoxyalkyl]3-azabicyclo[3.1.0]hexane chemotype with the introduction of substitution at the 6-position of the scaffold; previous work had demonstrated that there was no improvement in activity with substitution on the 5-position (Figure 28). The introduction of a CH2OMe group resulted in the identification of 120 as a lead molecule with greatly enhanced SERT/NET affinity and moderately enhanced DAT affinity relative to 61. The exoisomers 120 and 121 showed higher affinity than the endoisomer 119, consistent with the pharmacophore model. The more active enantiomer 120 of the exo-racemate showed low nanomolar affinity at both SERT and NET with ∼70-fold lower activity at DAT. Subsequently, several other 6-substitutions, including CH2OR (R: Et, CH2CF3, n-Pr, i-Pr, cyclopropyl, butyl, pentyl, etc.), were pursued while keeping either a 3,4dichlorophenyl or a 2-naphthyl group at the 1-position. Profiling of these compounds led to the discovery of 123, with CH2OEt as the preferred group (higher triple reuptake inhibitory activity than 120, an improved CYP inhibition profile with CYP2D6 IC50 4 μM and other isoforms >9 μM, and acceptable PK). Compound 123 showed >100-fold selectivity in a receptor panel assay and moderate hERG inhibitory activity (IC50: 4.2 μM). It showed a slow onset and a long-lasting increase of levels of 5-HT/NE/DA in the rat mPFC model (0.1−1.0 mpk ip). Following administration of 123 at 3, 10, and 30 mpk po, 5-HTP stereotyped behavior was significantly increased in a dose-dependent manner, consistent with SERT inhibition in vivo. Compound 123 significantly reduced immobility time in the mouse FST model at 3 and 10 mpk. The compound also showed significant locomotor activity at 10 2148



Perspective

Figure 30. Replacement of the side chain of 67 with (methylene) heteroaryls (GSK).

mpk ip in rats (microdialysis experiment) and significantly increased 5-HTP stereotyped behavior in a dose-dependent fashion over the range 3, 10, and 30 mpk, confirming in vivo inhibition of the 5-HT transporter. In the mouse FST model, 67 significantly reduced immobility time at all three of the doses tested (3, 10, and 30 mpk). In an ex vivo occupancy study, 67 showed a dose-dependent increase in SERT occupancy in the rat cortex while in an autoradiography experiment conducted in rats, the compound showed maximal SERT occupancy in almost all areas of the brain at a dose of 10 mpk. In a PET imaging study, the plasma concentration for half-maximal occupancy was found to be 15.16, 0.97, and 15.56 nM for SERT, NET, and DAT, respectively, in baboons, and 6.8 and 18 nM for SERT and DAT, respectively, in humans.121 This confirmed the penetration of 67 across the BBB and triple reuptake blockade in vivo. In a phase I clinical trial, 67 was well tolerated at doses up to 150 mg/day. However, development of 67 for MDD was discontinued for business reasons. Micheli et al. investigated the impact of replacement of the CH2OMe group of the clinical candidate 67 with C-linked heteroaryl or C-/N-linked, methylene-spaced heteroaryl substituents (Figure 30).122 Compound 142, designed by topological mapping of CH2OMe within a five-membered heterocycle, gave lower SERT affinity and higher NET/DAT affinity than 134. Replacement of the oxygen atom of 142 with a sulfur atom, a weaker H-bond acceptor, gave 143 which exhibited increased potency, a result consistent with the increase in clogP (3.8 vs 2.7), as explained by the authors. The racemate 143 showed subnanomolar activity (SERT/ NET/DAT ratio: 3/3/1) with a 40−50-fold separation in affinity between the enantiomers 144 and 145, respectively. Enantiomer 144, which imparted a balanced triple reuptake inhibition profile, showed weak CYP inhibition (IC50: >4 μM) and moderate intrinsic clearance in liver microsomes (human, rat: 2.6, 5.4 mL/min/g, respectively). The introduction of a methylene spacer between the 3-azabicyclo[4.1.0]heptane scaffold and the heteroaryl group in 142 and 143 resulted in

mpk, consistent with increased DA neurotransmission. Elongation of the CH2OMe moiety with the addition of a CH2 group afforded 126, which exhibited a 2−5-fold increase in SERT/NET/DAT activity compared to 120. Further modification by translocation of the aryl group led to an additional series based on a 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexane scaffold. Thus, translocation of the 3,4-dichlorophenyl group at the 1-position of 123 to the 6-position gave 128, which exhibited inferior NET potency. The endo-isomer 129 showed drastically reduced affinity compared to the exo-isomer 128, while homologation of the side chain of 128 was tolerated, as exemplified by 131. Further structural optimization by ring homologation led to the evolution of a third series based on the two regioisomeric derivatives, 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[4.1.0]heptane and 6-(aryl)-1-[alkoxyalkyl]-3-azabicyclo[4.1.0]heptane, that eventually paved the way for the identification of 67 as a candidate suitable for clinical development (Figure 29).91 Ring homologation of 61 resulted in regioisomers 132−133 and the regioisomeric 6-phenyl scaffold in 132 gave higher SERT/DAT potency relative to the 1-phenyl scaffold of 133. Further, the introduction of the CH2OMe group in 132 gave significantly higher affinity than in 133, affirming the superiority of the 6phenyl scaffold (compare 134 with 138). Translocation of the side chain from the 1-position in 134 to the 7-position, as in 136 and 137, resulted in significant reduction in TRI activity, suggesting the 1-position to be optimal. The regioisomer 136 with 6-(3,4-dichlorophenyl)-7-methoxymethyl substitution showed higher SERT potency but lower NET/DAT activity than the regioisomer 141 with a 1-(3,4-dichlorophenyl)-7methoxymethyl substituent. Replacement of the CH2OMe in 67 with CH2OEt gave 134 and 135, which exhibited almost superimposable activity profiles. Overall, 67 showed low nanomolar inhibitory activity, good selectivity (≥30-fold window with respect to DAT affinity) in a Cerep panel, and acceptable PK in rats. Compound 67 significantly elevated 5HT, NE, and DA levels in the mPFC and NAc at a dose of 3 2149



Perspective

Figure 31. Modification of the ring fusion of 67 to derive two different series of constrained arylpiperidines (GSK).

Figure 32. Optimization of substitutions at 4- and 7-positions of THIQ core resulting in the identification of 68 as a clinical candidate (AMRI/ BMS).

was replaced with electron-poor substituents including CF3 and CN (150, 151 and 154, 155). However, this change resulted in reduced NET/DAT affinity. The N-linked pyrroles 160−162 and heteroaromatics with >2 nitrogen atoms were also tolerated. The nitrile-substituted pyrrole analogues 161 and 162 showed somewhat similar profiles compared to the respective pyrazole counterparts 151 and 155. Benzo-fused systems 163 and 164, despite their bulky nature, were also tolerated. The indazole 164 gave higher SERT potency than the indole 163 possibly due to the presence of a potential H-bond acceptor. Modification of the ring fusion of 67 led to the discovery of two different series of constrained aryl piperidines. Profeta et al. reported 5-(3,4-dichlorophenyl)-4-[(methoxy)methyl]-2azabicyclo[3.2.1]octane derivatives as a new class of constrained 4-arylpiperidines with a more rigid C2 linkage, as summarized in Figure 31.123 All four isomers 165−168 gave relatively higher affinity for NET compared to SERT/NET. The anti-isomer 165 furnished the highest triple affinity with subnanomolar inhibitory activity at NET. The syn-isomers 167 and 168 showed a somewhat balanced profile in terms of relative potency in vitro. Another class of constrained oxa-azaspiro arylpiperidines was developed by exploiting the in-house pharmacophore model (Figure 20) and a hypothesis that an appropriately located tetrahydrofuran (THF)/tetrahydropyran (THP) moiety on the 4-phenylpiperidine scaffold would meet

lower DAT affinity in compounds 146 and 147. The homologated thiazole 147 furnished higher affinity than the corresponding oxazole derivative 146, consistent with the trend in clogP (compare with 142 and 143), as explained by the authors. Subsequently, N-linked heteroaryls were considered that offered an ease of synthesis in comparison to the C-linked heteroaryls. The N-linked pyrazoles demonstrated TRI profiles similar to the CH2OMe substituted analogues, although the affinity ratio was sensitive to the nature and position of substituents on the pyrazole ring. The 5-substituted pyrazole regioisomers 152−154 showed higher NET/DAT affinity than the corresponding 3-substituted regioisomers 148−150. The 4Me regioisomer 156 showed a significant reduction in NET/ DAT affinity, with a SERT/NET/DAT ratio of ∼1/100/100 compared to the more active enantiomers 149 and 153 of the 3- and 5-Me regioisomers. The introduction of a second Me group resulted in a further enhancement of SERT/NET potency, as exemplified by comparing 153 and 159. Compound 159 showed modest CYP inhibition (CYP2D6 IC50, 2 μM; other isoforms, >8 μM) and moderate to high clearance in liver microsomes (HLM, RLM: 2.4, 5.5 mL/min/g, respectively). In vivo, 159 showed a low bioavailability (F: 6%), a moderate Vd (6.9 L/kg), a moderate clearance (Clb: 52 mL/min/kg), a t1/2 of 2.3 h, and a B/P ratio of 0.8, consistent with the clearance determined in vitro. Assuming that the electron-rich pyrazole ring was responsible for metabolic clearance, the methyl group 2150



Perspective

Figure 33. Modification of the SNRI 19 to incorporate DAT activity (Mayo Clinic/Virginia Polytechnic Institute).

the requirements of the pharmacophore (Figure 31).124 The spiro-THP compound 170 was found to be more potent than the spiro-THF compound 169. Two more analogues, the oxetane 173 and the fused pyran 174, which were made to expand the scope, gave inferior triple affinity in agreement with the poor fit of these compounds in the pharmacophore model. The spiro-THP compound 170, which stood out in the series, was considered further with the profiling of its more active enantiomer 172, which showed weak CYP inhibition (CYP2D6 IC50, >4 μM; other isoforms, >10 μM) and low intrinsic clearance. However, it showed poor oral bioavailability in rats due to high hepatic extraction (90%) in spite of a high fraction of absorption (91%). 5.5. AMRI/BMS Series. A NDRI/TRI discovery program that was initiated between Albany Molecular Research Incorporated (AMRI) and DuPont Pharmaceuticals was subsequently acquired by Bristol-Myers Squibb (BMS) in 2001. Inspired by the structure of NDRI 24 as a prototype tetrahydroisoquinoline (THIQ), AMRI explored lead optimization to identify dual inhibitors (for depression or ADHD) that were devoid of aromatic amino group in an attempt to avoid toxicity reported for 24.10 This led to the identification of the NET/DAT inhibitor 175, which was later optimized with the aim of incorporating SERT activity (Figure 32).125 Investigation of diverse bicyclic heteroaryl groups on the 4position of THIQ resulted in the identification of 176 incorporating a benzothiophen-5-yl group, which showed low nanomolar triple reuptake inhibitory activity but with moderate CYP2D6 inhibition (IC50: 0.8 μM).125 In terms of stereogenic preference, the (+)-isomer 176 was found to be more potent than the (−)-isomer. The 5-position of the benzothiophene group in 176 as the attachment point gave better overall activity than the 2-, 3-, 6-, and 7-positions. Different substitutions at the 7-position while maintaining the benzothiophen-5-yl group intact at the 4-position of the THIQ nucleus were explored in an effort to reduce the CYP2D6 inhibitory activity. This resulted in the discovery of AMR-000002 (177) with a morpholino group at the 7-position as a highly potent TRI with weak CYP2D6 inhibition (IC50: 11 μM).125 Compound 177 showed significant and dose-dependent ex vivo occupancy at SERT (84−95%), NET (88−98%), and DAT (23−77%) in mice following oral dosing of 0.3, 1, and 3 mpk and significantly reduced immobility time in both the rat FST and mouse TST

models (MED: 1 mpk; po). It showed no significant activity at 1 μM against a broad panel of receptors and enzymes but displayed moderate hERG inhibitory activity (IC50: 1 μM). The compound showed no mutagenic potential and was orally bioavailable in the rat and cynomolgus monkey. In the monkey, an active N,O-dealkylated metabolite 178 was detected in significant amounts (>50%) in vivo,125 which indicated a potential DDI liability based on a CYP2D6 IC50 value of 1 μM and precluded further advancement of 177. AMRI out-licensed promising TRIs at the preclinical stage to Bristol-Myers Squibb to further develop and commercialize this chemotype for the treatment of major depression and neuropathic pain. The collaboration resulted in the advancement of 68 and BMS-866949 (structure not disclosed) into clinical trials. Compound 68, which arose from the THIQ series, reduced immobility time by 77% relative to placebo in the mouse TST model at a dose of 0.3 mpk.126 In a murine ex vivo model, 68 showed occupancy of 86%, 76%, and 28% for SERT, NET, and DAT, respectively, at a dose of 0.3 mpk. In a phase I clinical study, 68 demonstrated acceptable safety and tolerability in healthy subjects following oral administration (0.025−3.0 mg) with meaningful striatal SERT (0.5 and 3.0 mg: 19% and 82%, respectively) and DAT (3 mg: 19%) occupancies, slow absorption (tmax: 5.0−7.2 h), and a long t1/2 (34−57 h).127 The half-life supported once-daily administration and predicted drug accumulation upon repeated daily dosing. However, in a phase IIb clinical trial, 68 (0.25−2 mg) failed to demonstrate superior efficacy in patients with TRD when compared to 12 or 18.126 BMS-866949, another candidate from the collaboration, was progressed up to a phase I study that evaluated the compound in a multiple ascending dose trial.75 5.6. PRC Series. Using the SNRI 19 as the starting point, a collaborative team at the Mayo Clinic and Virginia Polytechnic Institute reported γ-aminoalcohol analogues designed to improve DAT affinity (Figure 33).128 Astra-Zeneca entered into an agreement to advance the best candidates into clinical development for the treatment of depression. The early compounds PRC025 (179; racemate) and PRC050 (180; racemate) showed higher triple transporter affinity than 19, with a pronounced effect on DAT.129 Compounds 179 and 180 significantly reduced the immobility time in both the mouse TST and rat FST models (5 and 10 mpk; ip), and the 2151



Perspective

Figure 34. Hybridization of the SNRI 182 and the TRI 61 to derive pyrrolidin-3-yl-1H-indole derivatives (Roche).

Figure 35. Lead optimization of 183, involving carbonyl insertion to mitigate the liabilities by lowering clogP and pKa (Roche).

30 mpk ip. Several modifications, including replacement of the indole moiety with other heteroaryls, introduction of substitution on the 2- or 3-position of indole ring, and replacement of the benzyl group, were subsequently explored. Isosteric replacement of the indole of 183 with an indazole or a benzothiophene was tolerated but offered no notable benefit. While the relocation of substitution at the 5-position of the indole ring to the adjacent 6-position was tolerated, further movement to the 3-position was less well tolerated. Introduction of substitutions at the 2- or 3-position of the indole ring (183) improved the metabolic stability by reducing microsomal clearance. Out of several substitutions (CN, CO2Et, CONH2, CONHMe, CONMe2), the introduction of a CONH2 moiety at the 2-position in 183 resulted in the desired balanced activity profile (SERT/NET/DAT Ki: 2/9/18 nM), higher metabolic stability (HLM: 1.4 μL/min/mg), reduced CYP2D6 DDI potential (IC50: 4.1 μM), and weak hERG inhibition (IC50: > 10 μM) but reduced permeability with a higher efflux ratio [ER] of 28, which would limit CNS exposure. Among the alkyl groups evaluated as benzyl replacements, the n-Bu group in 70 (RG-7166) gave the best potency along with acceptable in vitro characteristics (CYP2D6 IC50, 3.4 μM; hERG IC50, 4.4 μM; Papp A−B, 9.4 × 10−6 cm/s) but with a high metabolic clearance (HLM: 38 μL/min/mg). Although phase I development of 70 began in 4Q 2009, the compound was discontinued in 2012.75 To further mitigate metabolic clearance, CYP inhibition, and hERG liability, lowering of the clogP and pKa was achieved by insertion of a carbonyl group into 183 (Figure 35).132 Compared to 183, the ketopyrrolidine 186 showed similar SERT/DAT affinity, reduced NET activity, significant improvement in HLM stability, reduced hERG inhibition (IC20: 6.1 μM), and excellent permeability (Papp A−B: 17 × 10−6 cm/s). This inspired a multipronged structural modification effort

antidepressant-like effect was comparable to that of 5 at a dose of 15 mpk (ip). Chiral separation of 180 provided 69 and PRC201-RR (181).85 Compound 69 showed SERT/NET-preferring triple reuptake inhibitory activity, with good selectivity (Ki > 1 μM) against a CNS receptor panel that included 5-HT, NE, DA, histamine, and muscarinic receptors. Compound 69 produced a significant increase in the extracellular levels of 5-HT, and NE in the PFC and DA and 5-HT in the NAc with a decrease in the levels of 2,4-dihydroxyphenylacetic acid (DOPAC), HVA, and 5-HIAA in rats at doses of 5 or 10 mpk ip. In the rat FST model, doses of 1, 5, and 10 mpk (ip) of 69 induced a dosedependent reduction of immobility, with the effect at 1 mpk comparable to that of a 15 mpk dose of imipramine (5). A similar dose-dependent reduction in the immobility time was observed in the mouse TST model following ip administration of the drug and 69 produced no significant locomotor activity in rats at 1 and 10 mpk. In toxicological studies, 69 produced dose-proportional kidney (distal tube) toxicity in cynomolgus monkeys, consistent with the urinary elevation of the biomarker calbindin D28.130 5.7. Roche Series. TRI discovery program at Roche was an extension of the SNRI program that led to the successful introduction of 18 in the market. Bannwart et al. recently reported a series of 3,3-disubstituted pyrrolidine derivatives which were arrived at by combining two discrete substructures from indolyl phenylpropanolamine (182; SNRI, Roche internal lead) and 61 (Figure 34).131 Interestingly, the first compound 183 showed significantly higher triple potency than 61 and favorable in vitro permeability and hERG inhibition, but human microsomal stability was low and there was significant inhibition of CYP2D6. The (+)-enantiomer 184, which was found to be the more active enantiomer of 183, showed an antidepressant-like effect in the mouse TST model at a dose of 2152



Perspective

Figure 36. Chirality elimination and scaffold hopping as key strategies to design substituted piperidine and piperazine derivatives and the putative mechanism of TDI liability of the series (Roche).

the piperidine, benzyl, and metabolically labile indole were modified, was undertaken. However, these optimization efforts failed to afford a compound with the targeted product profile due to the liabilities associated with CYP2D6, CYP3A4, and/or hERG inhibition. Moreover, 193 was found to be inactive in a locomotor assay (LMA) and the TST model conducted in mice at 30 mpk, which was in line with the absence of DAT occupancy (0%) in mice. This might be attributable to an insufficient unbound concentration of 193 in the striatum to effectively occupy DAT. A scaffold hopping strategy was pursued in an effort to reduce the pKa by designing the 2substituted piperazine 194, assuming that it would help to improve membrane permeability, brain exposure, and efficacy in vivo. Compound 194 was active in both the LMA and TST models (MED: 10 mpk), which was consistent with the high DAT occupancy (75%) observed in mice. This was likely due to the 5-fold higher free fraction of 194 in the brain compared to 193 (206 vs 37 nM). Because both 193 and 194 were not P-gp substrates, this result suggested that pKa played a key role in boosting the free fraction of 194 in the brain. Because of the likely contribution of the 2,3-unsubstituted indole ring to the observed low metabolic stability (HLM: 43.3 μL/min/mg), modification of this potential soft spot was considered. Replacement of indole with phenyl, dichlorophenyl, and Nmethylindole gave reduced NET and/or DAT affinity, suggesting a requirement for an indole-like chemotype for Hbonding interactions. Replacement of the indole of 194 with an indazole gave 195, which resulted in improved metabolic stability (HLM: 3.8 μL/min/mg) while maintaining good potency. However, 195 showed potent CYP2D6 inhibition (IC50: 0.05 μM). While maintaining the indazole ring, replacing the benzyl with other groups (Ph, PhCH2CH2, alkyl, and others) was considered in an effort to develop improved CYP2D6 inhibition SARs, which afforded compound 196 with a low CYP2D6 DDI liability, albeit with reduced NET affinity.134 However, the indole and indazole compounds (e.g., 196) showed CYP3A4 time-dependent inhibition (TDI) potential in vitro, possibly through the formation of diiminoquinones (e.g., 198) as reactive metabolites. Even though optimized analogues were identified with a lower risk of CYP3A4-mediated TDI, the potential of these compounds to undergo N-acetylation to give 197 in vivo and the heightened

involving the pyrrolidine, benzyl, and indole elements. While replacement of the 3-pyrrolidine ring in 186 with a 3-azetidine or a 3-azepine resulted in a loss of potency, piperidine analogues showed acceptable potency but with either P-gpmediated efflux (4-piperidine) or strong CYP2D6 and hERG inhibition (3-piperidine) as potential liabilities. This suggested retention of the 3-pyrrolidine group while optimizing the other elements. Further SAR development led to the identification of the 7-fluoroindole derivative 187 which exhibited good potency, metabolic stability, and permeability. Compound 187 showed antidepressant-like activity in the mouse TST model at doses of 10−30 mpk ip. Replacing the benzyl group with alkyl groups resulted in the identification of 188, which incorporates a dimethylbutyl group and exhibits picomolar SERT inhibitory activity, moderate clearance, and somewhat weak CYP2D6 inhibition. Modification of the indole heterocycle by isosteric replacement, while retaining the pyrrolidine and dimethylbutyl groups, was investigated as a means of reducing the CYP2D6 inhibition liability. This resulted in the identification of several compounds with promising in vitro triple affinity profiles that incorporated substituted monoaryls and heteroaryls and bicyclic heteroaryls. Representative compound 189 furnished excellent inhibition (triple reuptake inhibitory Ki < 10 nM), acceptable SERT/DAT occupancy in rats (80/20% at 1.15 mpk ip) suggestive of good brain penetration, and good oral bioavailability in rats. The difficulty with enantioselective synthesis or separation of enantiomers in the earlier work (vide supra) prompted the design of achiral aminoheterocycles (Figure 36).133 However, abolishment of the chiral center by introducing a nitrogen atom into the Roche lead 190 resulted in a significant loss of triple reuptake inhibitory activity, as exemplified by the profile of 191. Constraining the side chain via piperidine analogues was subsequently explored (partly to mitigate any potential Ndemethylation metabolism), which led to a further loss of triple reuptake inhibitory activity in 192. However, the introduction of a methylene spacer to the aminopiperidine exonitrogen resulted in a significant increase in triple inhibitor potency as exemplified by 193. This compound showed acceptable HLM stability and permeability but with undesirable hERG (IC20: 1 μM) and CYP2D6 (IC50: 0.1 μM) inhibition. In an attempt to address these deficiencies, a three-pronged approach, in which 2153



Perspective

Figure 37. Design of diazepanone derivatives with low potential for CYP2D6 and hERG inhibition (Takeda).

Figure 38. Design of 4-benzylpiperidine derivatives with low risk for CAD-associated or other safety liabilities (Takeda).

risk of N-acetyl metabolites like 199 for TDI of CYP3A4 prompted a deprioritization of this series. 5.8. Takeda Series. A ligand-based drug design approach was employed to arrive at 1-aryl-1,4-diazepan-2-one derivatives as hybrid compounds of 21 (SNRI) and 61 (Figure 37).135 The initial compound 200 was built to include the key structural features of an aryl ring, a basic amine, and an amide moiety and showed higher affinity for NET than SERT and DAT. Cyclization of 200 to give 201 resulted in improved NET/ DAT affinity. Removal of the cyclopropyl group in 201 gave the benchmark compound 202 with improved SERT/NET activity but decreased DAT activity and lower metabolic stability. To enhance the metabolic stability, substitutions including F, Me, and Et were investigated on the diazepan-2-one ring of 202 while keeping 3,4-dichlorophenyl as the aryl ring. The introduction of a Me group at the 3-position (203) was found to be optimal for triple reuptake inhibitory activity, while Me substitution at other positions was poorly tolerated. Compound 203 showed higher metabolic stability than 202. Replacement of the 3,4-dichlorophenyl moiety with a 2naphthyl group gave compound 204 with enhanced SERT/ NET activity and an acceptable metabolic profile. Chiral separation of 204 provided enantiomer 205, which was characterized by low MW ( SERT > DAT. Replacement of the phenyl with a 3,4-dichlorophenyl or a 2naphthyl group (245−246), led to improved triple reuptake inhibitory activity in the case of the (−)-isomers, while the corresponding (+)-isomers (247−248) displayed lower potency. On the basis of an early series of reuptake inhibitors explored at Lilly that featured a bicyclo[2.2.2]octane template (e.g., 249), analogues with a bicyclo[2.2.1]heptane architecture were 2157



Perspective

Figure 48. Evolution of 1,3-diamino-1-arylpropane derivatives.

mpk) showed lower acute toxicity than the threo-isomers 260 and 262 (LD50: 200−400 mpk). Structural modification of 259 led to the identification of arylpropanol piperidine derivatives with 263 and 264 as representatives.156 These compounds showed a significant and dose-dependent (10, 20, and 50 mpk; po) reduction of immobility in the mouse TST model. The compounds did not produce locomotor activity at the highest efficacious dose (50 mpk), suggesting that the antidepressantlike effect was not due to motor stimulation. Neither 263 nor 264 showed significant activity in a Cerep panel of CNS receptors. In rats, 263 and 264 showed good oral bioavailability (F: 44−56%) at a dose of 10 mpk. Structural modification of the arylalkanol piperidine chemotype led to a series of arylalkyl diamine derivatives where the 3,4-dichlorophenyl group at the C-1 position was found to be important for good triple transporter inhibition157 Select compounds 265−267 showed a statistically significant and dose-dependent reduction in immobility time in the rat FST at doses of 5, 10, and 20 mpk (po). These compounds did not alter motor activity at 20 mpk, suggesting that the antidepressant-like effect was not due to motor stimulation. In the Cerep panel of CNS receptors, 265 did not show any significant inhibition except for SERT, NET, and DAT. In a single dose toxicology study, 265 caused mortality in 60% of mice at a dose of 900 mpk, whereas lower doses of 150−450 mpk caused no abnormalities or death after 2 weeks of drug administration. Compound 265 was negative in an Ames test. At a dose of 2 mpk, 265 showed moderate oral bioavailability (F: 19%), and after a dose of 0.5 mpk ip, the B/P ratio was found to be 23 in rats.

ition in the order of SERT > NET > DAT with a comparable behavioral and neurochemical profile to the TRI 59. In both the FST and TST (mouse) models, 254 reduced immobility time at doses of 30 and 60 mpk but not at 15 mpk. This observation was consistent with microdialysis results, which revealed that significant elevation of monoamines in the mouse PFC was observed at doses of 30 and 60 mpk but not at 15 mpk. Drug discrimination studies in cocaine-treated rats indicated that both 254 and 59 partially substituted for cocaine. Unlike 59, 254 did not induce either locomotor stimulation upon shortterm administration or locomotor sensitization upon repeated administration at the efficacious doses. Han et al. explored 3-substituted azetidines, designed by the rigidification of the 3-aryl-3-oxypropylamine scaffold that is common to several monoamine reuptake inhibitors (Figure 47).152 Compounds bearing a naphthyl ring as the R 1 substituent gave very high potency. Bulky R2 groups like n-Pr or aryl gave higher activity than smaller groups like Me and Et. Representative compounds 255−256 showed good reuptake inhibition with modest CYP and hERG inhibition and were progressed for profiling in vivo. The compounds showed a reasonable B/P ratio (255, 0.9; 256, 2.7), but poor oral bioavailability (F < 6%) in rats. Compound 256 showed a dosedependent reduction of immobility time in the mouse FST model (iv and po). Further extension of this work was recently reported with the identification of 257, which showed good potency with modest CYP and hERG inhibition.153 The elimination of chirality by bioisosteric modification of 3-αoxyazetidines to render 3-aminoazetidines and their homologated analogues was subsequently explored to avoid cumbersome chiral resolution/synthesis (Figure 47).154 The SERT-preferring lead compound 258 showed lower inhibition of CYP1A2, CYP2D6, and CYP3A4 (IC50 values >1 μM) than 18, weak hERG inhibition (IC50: 5.5 μM), and no promutagenic or mutagenic effect. Compound 258 showed an adequate B/P ratio (2.09) and moderate oral bioavailability (F: 28%) in rats. Li et al. reported the synthesis and pharmacological evaluation of SIPI5056 (259) and its isomers 260−262 (Figure 48).155 While 259 showed high triple reuptake inhibitory potency with the order of SERT > NET > DAT, the isomers 260−262 showed lower activity at SERT/NET and were inactive at DAT. Consistent with the inhibition in vitro, 259 showed the antidepressant-like efficacy with ED50 values of 12.6 and 2.9 mpk (po) in the mouse TST and FST models, respectively. The erythro-isomers 259 and 261 (LD50: >1000

■

CONCLUSIONS AND FUTURE PROSPECTS Currently, 350 million people globally are believed to be affected by unipolar depression, and this devastating disease is predicted to become the single biggest health burden in the next decade. Unfortunately, about 35% of depressed patients are not adequately treated by marketed drugs, resulting in the existence of a large unmet clinical need. Despite a large patient population and a huge unmet medical need, the antidepressant pipeline is relatively sparse with few candidates in development. The exact reasons for the suboptimal response to SoC (SSRI and SNRIs) with low remission rates and persistent residual symptoms are currently unknown but assumed to be the absence of a pharmacological effect of these agents on other impaired pathways. A substantial body of evidence accrued from preclinical and clinical studies supports the hypofunction of dopamine tone in the pathophysiology of depression. The 2158



Perspective

case of 68, for which both SERT and DAT occupancies were determined, it is possible that 68 could have acted largely as a SNRI in humans due to the possibility of low DAT occupancy at the clinical dose of 2 mg (compare 19% after a single 3 mg dose in healthy subjects). Clinical NET occupancy was not determined for any of the compounds, likely due to the limited availability of NET-selective PET ligands at that time. NET occupancy data would have provided clarity about whether the cardiovascular side effects of some of the clinical compounds, especially at higher doses, was due to a high level of NET inhibition. Going forward, it appears to be indispensable to have strong translational evidence before progressing a compound into phase II clinical trials. Foremost, it is important to understand whether TRIs demonstrate adequate SERT/NET/DAT occupancy through PET imaging studies in healthy or MDD subjects to give sufficient confidence. Moreover, PET occupancy, which allows the correlation of target occupancy with plasma/free drug concentration in vivo, may inform early decision making about dose selection and therapeutic potential for various indications. Confirmation of appropriate levels of target engagement in rodents and/or nonrodents will be useful for decision making, although it cannot substitute for the clinical confirmation of target occupancy due to potential crossspecies differences. TRIs were progressed to clinical trials based on the observation of antidepressant-like effects in animal models, but the failure of translation of preclinical efficacy to the clinic raises questions about the predictive validity of these models. From a development perspective, the biggest challenge is the identification of the optimal ratio of triple reuptake inhibition for an effective therapeutic response without addictive and other liabilities, and this still is not known. This is further complicated by the inconsistencies between in vitro activity and in vivo clinical outcome (target occupancy/monoamine biomarker concentration) of the compounds, as observed in the cases of 65 and 66. This further underscores the importance of a PET study as a prerequisite for a phase II clinical trial. The current level of understanding based on clinical PET occupancy studies suggests a preference in the order of SERT > NET > DAT occupancy. However, caution needs to be exercised as this order of preference was mainly evolved based on the occupancy of selective agents at the individual transporters. The clinically appropriate relative target occupancies upon the administration of multimodal TRIs, considering the synergistic and antagonistic effect of DAT inhibition upon the inhibition of SERT/NET, remain to be determined. Evidence for central engagement of monoamine transporters by measuring monoamine biomarkers (monoamines and their primary metabolites) in the CSF of healthy or depressed subjects may add weight to the occupancy data to aid informed decisions for phase II progression. The nature of DA signaling may also influence the outcome of antidepressant efficacy. Considering those TRIs that had long half-life and failed to offer significant clinical benefit in spite of addition of DAT pharmacology and antidepressant efficacy of psychostimulants, one can assume that depressive symptoms might be best relieved by phasic DA signaling (similar to that of psychostimulants) rather than the steady DA tone likely to be provided by the long-half-life−slow-onset properties of current TRIs. Importantly, it is essential that clinical candidates demonstrate adequate tolerability without dose-limiting safety issues,

inducement of DA dysfunction has been shown to produce depressive symptoms, and the correction of DA dysfunction by dopaminergic agents has been shown to alleviate depression in some clinical studies. On the basis of these data, TRIs, which concurrently elevate DA along with 5-HT and NE, would be expected to demonstrate therapeutic benefit. DA is expected to play a dual role of potentiating the therapeutic benefit of SSRIs/SNRIs and opposing the side effects of SERT blockade. As a consequence, TRIs have been hypothesized to increase the rate of remission, reduce the time of therapeutic lag, and alleviate the residual symptoms of treatment with SSRIs/ SNRIs. Importantly, such a polypharmacological treatment strategy seems relevant in the context of the complex etiology and polygenetic nature of a mental illness like depression. Medicinal chemistry efforts have led to the identification of at least 10 clinical candidates, numerous preclinical candidates, and the publication of ∼150 patent applications. Two different medicinal chemistry strategies have been adopted that have either involved structural modification of selective reuptake inhibitors to broaden their effects to encompass triple reuptake activity or the exploitation of known TRIs (e.g., 27, 73, and 61) to improve their properties. The history of successful development of single or dual reuptake inhibitors fostered confidence to extend efficacy into the TRI paradigm with compounds from internal collections often serving as the starting points. The salient features of a TRI pharmacophore include a positive ionizable group and 2−3 hydrophobic regions with the fundamental requirement of basic amine. The basic amine typically contributes to hERG and CYP2D6 liabilities, which has necessitated extensive structural optimization efforts. TRI compounds with a diverse spectrum of in vitro triple affinities have been advanced into clinical trials. Contrary to expectations, the outcomes from several phase II clinical trials of TRIs have not been promising. In MDD patients, compounds 59 and 68 demonstrated efficacy that was similar to active controls while 64 and 65 failed to differentiate from placebo. Although 59 showed significant efficacy with attenuation of anhedonic symptoms in a PoC clinical trial, it failed to show efficacy in a subsequent trial in MDD subjects with TRD. Overall, these clinical candidates demonstrated a lack of statistically significant efficacy compared to placebo or failed to differentiate from standard of care. This is a setback to the development of TRIs as novel medicines and has discouraged the development of additional candidates. Assuming a therapeutic benefit of adding DAT inhibition to the profile of mono and dual reuptake inhibition therapies, the suboptimal performance of clinical candidates may be assigned, based on the available data, to three key reasons: (1) suboptimal target engagement, (2) an inadequate dosing regimen, and (3) safety (intolerability) concerns. Compound 61 showed a potentially inadequate level of SERT occupancy of 48% at a dose of 150 mg, which was suggested to be one of the reasons for poor clinical efficacy.158 While 64 showed high SERT and DAT occupancies after doses of 1−2 mg, it was not well tolerated, with the observation of significant side effects which might have clouded the potential to observe efficacy. It is not known whether extensive DAT inhibition (60−80% occupancy) was one of the reasons for poor tolerability. Compound 65 showed inadequate SERT occupancy of 2−14% at doses that were at least 4-fold higher than the highest clinical dose for efficacy studies, which might have contributed to the inferior clinical response. In addition, plasma exposure was well below those observed in several phase I clinical trials. In the 2159



Perspective

especially cardiovascular side effects. Any dose-limiting intolerability may negatively impact the clinical outcome in depressed patients and potentially force the use of doses inadequate for the desired level of target engagement. Another critical factor for the successful development of TRIs is the clinical demonstration of low potential for abuse. On a positive note, all of the tested TRIs (69, 63, 62, and 65) have shown limited abuse potential in preclinical or clinical studies. Hence, abuse potential, which appears to be controllable by the characteristic occupancy-PK pattern of current TRI candidates (modest DAT occupancy, slow onset of DAT occupancy, or late tmax, and long half-life), may not be a significant issue at this juncture. General factors that can potentially affect the efficacy in the clinical trials include placebo effect, subjective and insensitive rating scales, and heterogeneity of the patient population. While patient heterogeneity requires large and complex clinical trials, improved patient stratification may eliminate the necessity for the large trials.159 Stratification of depressive or TRD patients with a subset of anhedonic symptoms, reward network dysfunction, a high burden of reduced positive state, and psychomotor retardation, may improve clinical outcome, as these patients are expected to demonstrate reduced DA turnover.4 In short, the successful development of TRIs will depend on strong translational evidence (e.g., target engagement in depressed subjects; impact on clinical biomarkers connected to the disease pathophysiology), optimal dosing regimen to support adequate target occupancy, adequate safety margin, and differentiated clinical outcome for dopaminergic impairment through an appropriate clinical study design. Beyond depression, TRIs hold potential to treat a wide range of medical conditions, in which the deficiency of monoamines has been implicated, including ADHD, pain, AUD, cocaine addiction, BED, and obesity, with four candidates currently under clinical development. It is hoped that the right combination of TRI profile, drug-like properties, and appropriate therapeutic indications will soon be identified to enable patients to benefit from the potential of these promising agents.

■

oncology. His current research focusses on prodrug-mediated drug delivery, macrocyclic peptides, and chemogenomics.

■

ACKNOWLEDGMENTS I thank Nicholas A. Meanwell (N.A.M.), Richard Olson (R.O.), John E. Macor, Ramakanth Sarabu (R.S.), and Murugesan Natesan (M.N.) from Bristol-Myers Squibb for strong support. I am deeply grateful to N.A.M. and R.O. for an in-depth review of this manuscript, constructive comments, and valuable insights. I also thank Michael Weed, Michael Sinz, M.N., and R.S. for their suggestions.

■

ABBREVIATIONS USED AD, Alzheimer’s disease; ADHD, attention deficit hyperactivity disorder; AUD, alcohol use disorder; BED, binge eating disorder; B/P, brain to plasma; CAD, cationic amphiphilic drug; CD, catecholamine depletion; CMS, chronic mild stress; CSF, cerebrospinal fluid; DIO, diet-induced obesity; DHPG, 3,4-dihydroxyphenylglycol; DRI, dopamine reuptake inhibitor; FSL, Flinders sensitive line; FST, forced swimming test; 5HIAA, 5-hydroxyindoleacetic acid; 5-HT, serotonin; HLM, human liver microsomes; HVA, homovanillic acid; ICSS, intracranial self-stimulation; MAO, monoamine oxidase; MAOI, monoamine oxidase inhibitor; MDD, major depressive disorder; MED, minimum effective dose; mpk, mg/kg; NAc, nucleus accumbens; NDRI, norepinephrine dopamine reuptake inhibitor; NE, norepinephrine; NET, norepinephrine transporter; NRI, norepinephrine reuptake inhibitor; PD, Parkinson’s disease; PET, positron emission tomography; PFC, prefrontal cortex; PoC, proof of concept; PTSD, post-traumatic stress disorder; rac, racemate; RLM, rat liver microsomes; RMDD, remitted major depressive disorder; SoC, standard of care; s.e., single enantiomer; SNRI, serotonin norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; TDI, timedependent inhibition; TRD, treatment-resistant depression; TRI, triple reuptake inhibitor; TST, tail suspension test; VMAT-2, vesicular monoamine transporter-2; VTA, ventral tegmental area

■

AUTHOR INFORMATION

Corresponding Author

REFERENCES

(1) Depression Fact Sheet; World Health Organization (WHO): Geneva, 2017; http://www.who.int/mediacentre/factsheets/fs369/ en/ (accessed May 29, 2017). (2) Antidepressant Use in Persons Aged 12 and Over: United States, 2005−2008; National Center for Health Statistics: Atlanta, 2011; https://www.cdc.gov/nchs/products/databriefs/db76.htm (accessed May 29, 2017). (3) Calderone, J. The Rise of All-Purpose Antidepressants; Scientific American November 1, 2014; https://www.scientificamerican.com/ article/the-rise-of-all-purpose-antidepressants/ (accessed May 29, 2017). (4) Lane, R. M. Antidepressant drug development: focus on triple monoamine reuptake inhibition. J. Psychopharmacol. 2015, 29, 526− 544. (5) Stahl, S. M. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 4th ed.; Cambridge University Press: New York, 2013. (6) Dunlop, B. W.; Nemeroff, C. B. The role of dopamine in the pathophysiology of depression. Arch. Gen. Psychiatry 2007, 64, 327− 337. (7) Marks, D. M.; Pae, C.-U.; Patkar, A. A. Triple reuptake inhibitors: the next generation of antidepressants. Curr. Neuropharmacol. 2008, 6, 338−343.

*Phone: +91-(0)9655598704. E-mail: murugaiah.andappan@ syngeneintl.com. ORCID

Murugaiah A. M. Subbaiah: 0000-0001-5707-966X Notes

The author declares no competing financial interest. Biography Murugaiah A. M. Subbaiah received his Ph. D. degree under the supervision of Dr. Mukund Gurjar from the National Chemical Laboratory in 2000. His research focused on carbohydrate chemistry and asymmetric synthesis for CMI-977 and its analogues. Subsequently, he pursued postdoctoral research of the discovery of AT2 agonists and oxidative Heck chemistry under Prof. Anders Hallberg and Prof. Mats Larhed at the Department of Medicinal Chemistry, Uppsala University. In 2004, he joined the Department of Medicinal Chemistry, New Drug Discovery Research at Ranbaxy. Since 2008, he has been working at the Biocon-BMS R&D Centre. He has had the opportunity to work in therapeutic areas including CNS (depression and anxiety), metabolic disorders, infectious diseases, and 2160



Perspective

(8) Patel, K.; Allen, S.; Haque, M. N.; Angelescu, I.; Baumeister, D.; Tracy, D. K. Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Ther. Adv. Psychopharmacol. 2016, 6, 99−144. (9) Bupropion; Wikipedia, 2017; https://en.wikipedia.org/wiki/ Bupropion (accessed May 29, 2017). (10) Pechulis, A. D.; Beck, J. P.; Curry, M. A.; Wolf, M. A.; Harms, A. E.; Xi, N.; Opalka, C.; Sweet, M. P.; Yang, Z.; Vellekoop, A. S.; Klos, A. M.; Crocker, P. J.; Hassler, C.; Laws, M.; Kitchen, D. B.; Smith, M. A.; Olson, R. E.; Liu, S.; Molino, B. F. 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 7219−7222. (11) Gaynes, B. N.; Warden, D.; Trivedi, M. H.; Wisniewski, S. R.; Fava, M.; Rush, A. J. What did STAR*D teach us? results from a largescale, practical, clinical trial for patients with depression. Psychiatr. Serv. 2009, 60, 1439−1445. (12) Sim, K.; Lau, W. K.; Sim, J.; Sum, M. Y.; Baldessarini, R. J. Prevention of relapse and recurrence in adults with major depressive disorder: systematic review and meta-analyses of controlled trials. Int. J. Neuropsychopharmacol. 2016, 19, pyv076. (13) Best, J. A.; Nijhout, H. F.; Reed, M. C. Homeostatic mechanisms in dopamine synthesis and release: a mathematical model. Theor. Biol. Med. Modell. 2009, 6, 21. (14) McHugh, P. C.; Buckley, D. A. The structure and function of the dopamine transporter and its role in CNS diseases. Vitam. Horm. 2015, 98, 339−369. (15) Efimova, E. V.; Gainetdinov, R. R.; Budygin, E. A.; Sotnikova, T. D. Dopamine transporter mutant animals: a translational perspective. J. Neurogenet. 2016, 30, 5−15. (16) Sinita, E.; Coghill, D. The use of stimulant medications for noncore aspects of ADHD and in other disorders. Neuropharmacology 2014, 87, 161−172. (17) Cheng, M. H.; Cobanoglu, M. C.; Bahar, I.; Block, E.; Sorkin, A.; Hu, F. Insights into the modulation of dopamine transporter function by amphetamine, orphenadrine, and cocaine binding. Front. Neurol. 2015, 6, 134. (18) Andersen, M. L.; Kessler, E.; Murnane, K. S.; McClung, J. C.; Tufik, S.; Howell, L. L. Dopamine transporter-related effects of modafinil in rhesus monkeys. Psychopharmacology (Berl.) 2010, 210, 439−448. (19) Kim, W.; Tateno, A.; Arakawa, R.; Sakayori, T.; Ikeda, Y.; Suzuki, H.; Okubo, Y. In vivo activity of modafinil on dopamine transporter measured with positron emission tomography and [(1) (8)F]FE-PE2I. Int. J. Neuropsychopharmacol. 2014, 17, 697−703. (20) Perona, M. T.; Waters, S.; Hall, F. S.; Sora, I.; Lesch, K. P.; Murphy, D. L.; Caron, M.; Uhl, G. R. Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions. Behav. Pharmacol. 2008, 19, 566−574. (21) Tye, K. M.; Mirzabekov, J. J.; Warden, M. R.; Ferenczi, E. A.; Tsai, H.-C.; Finkelstein, J.; Kim, S.-Y.; Adhikari, A.; Thompson, K. R.; Andalman, A. S.; Gunaydin, L. A.; Witten, I. B.; Deisseroth, K. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 2013, 493, 537−541. (22) Witkin, J. M.; Monn, J. A.; Schoepp, D. D.; Li, X.; Overshiner, C.; Mitchell, S. N.; Carter, G.; Johnson, B.; Rasmussen, K.; RorickKehn, L. M. The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J. Pharmacol. Exp. Ther. 2016, 358, 71−82. (23) Willner, P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiology of Stress 2017, 6, 78−93. (24) Papp, M.; Gruca, P.; Lason-Tyburkiewicz, M.; Adham, N.; Kiss, B.; Gyertyan, I. Attenuation of anhedonia by cariprazine in the chronic mild stress model of depression. Behav. Pharmacol. 2014, 25, 567−574. (25) Roth-Deri, I.; Friedman, A.; Abraham, L.; Lax, E.; Flaumenhaft, Y.; Dikshtein, Y.; Yadid, G. Antidepressant treatment facilitates dopamine release and drug seeking behavior in a genetic animal model of depression. Eur. J. Neurosci. 2009, 30, 485−492.

(26) Salamone, J. D.; Yohn, S. E.; Lopez-Cruz, L.; San Miguel, N.; Correa, M. Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology. Brain 2016, 139, 1325−1347. (27) Yohn, S. E.; Gogoj, A.; Haque, A.; Lopez-Cruz, L.; Haley, A.; Huxley, P.; Baskin, P.; Correa, M.; Salamone, J. D. Evaluation of the effort-related motivational effects of the novel dopamine uptake inhibitor PRX-14040. Pharmacol., Biochem. Behav. 2016, 148, 84−91. (28) Randall, P. A.; Lee, C. A.; Podurgiel, S. J.; Hart, E.; Yohn, S. E.; Jones, M.; Rowland, M.; Lopez-Cruz, L.; Correa, M.; Salamone, J. D. Bupropion increases selection of high effort activity in rats tested on a progressive ratio/chow feeding choice procedure: implications for treatment of effort-related motivational symptoms. Int. J. Neuropsychopharmacol. 2015, 18, pyu017. (29) Owesson-White, C. A.; Cheer, J. F.; Beyene, M.; Carelli, R. M.; Wightman, R. M. Dynamic changes in accumbens dopamine correlate with learning during intracranial self-stimulation. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 11957−11962. (30) Miller, L. L.; Leitl, M. D.; Banks, M. L.; Blough, B. E.; Negus, S. S. Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats. Pain 2015, 156, 175−184. (31) Basso, A. M.; Gallagher, K. B.; Bratcher, N. A.; Brioni, J. D.; Moreland, R. B.; Hsieh, G. C.; Drescher, K.; Fox, G. B.; Decker, M. W.; Rueter, L. E. Antidepressant-like effect of D(2/3) receptor-, but not D(4) receptor-activation in the rat forced swim test. Neuropsychopharmacology 2005, 30, 1257−1268. (32) Prica, C.; Hascoet, M.; Bourin, M. Is co-administration of bupropion with SSRIs and SNRIs in forced swimming test in mice, predictive of efficacy in resistant depression? Behav. Brain Res. 2008, 194, 92−99. (33) Kunugi, H.; Hori, H.; Ogawa, S. Biochemical markers subtyping major depressive disorder. Psychiatry Clin. Neurosci. 2015, 69, 597− 608. (34) Pizzagalli, D. A. Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu. Rev. Clin. Psychol. 2014, 10, 393−423. (35) Whitton, A. E.; Treadway, M. T.; Pizzagalli, D. A. Reward processing dysfunction in major depression, bipolar disorder and schizophrenia. Curr. Opin. Psychiatry 2015, 28, 7−12. (36) Wardle, M. C.; Treadway, M. T.; Mayo, L. M.; Zald, D. H.; de Wit, H. Amping up effort: effects of d-amphetamine on human effortbased decision-making. J. Neurosci. 2011, 31, 16597−16602. (37) D’Ostilio, K.; Garraux, G. The network model of depression as a basis for new therapeutic strategies for treating major depressive disorder in Parkinson’s disease. Front. Hum. Neurosci. 2016, 10, 161. (38) Treadway, M. T.; Pizzagalli, D. A. Imaging the pathophysiology of major depressive disorder - from localist models to circuit-based analysis. Biol. Mood Anxiety Disord. 2014, 4, 5. (39) Sarchiapone, M.; Carli, V.; Camardese, G.; Cuomo, C.; Di Giuda, D.; Calcagni, M.-L.; Focacci, C.; De Risio, S. Dopamine transporter binding in depressed patients with anhedonia. Psychiatry Res., Neuroimaging 2006, 147, 243−248. (40) Wooten, D.; Goer, F.; Beltzer, M.; Vitaliano, G.; Brennan, B.; Crowley, D.; Alpert, N.; Normandin, M.; El Fakhri, G.; Pizzagalli, D. Reduced striatal dopamine transporter binding in major depressive disorder. J. Nucl. Med. 2015, 56, 527. (41) Wu, H.; Lou, C.; Huang, Z.; Shi, G. SPECT imaging of dopamine transporters with 99mTc-TRODAT-1 in major depression and Parkinson’s disease. J. Neuropsychiatry Clin. Neurosci. 2011, 23, 63−67. (42) Felger, J. C. The role of dopamine in inflammation-associated depression: mechanisms and therapeutic implications. Curr. Top. Behav. Neurosci. 2016, 31, 199−219. (43) Hasler, G.; Luckenbaugh, D. A.; Snow, J.; Meyers, N.; Waldeck, T.; Geraci, M.; Roiser, J.; Knutson, B.; Charney, D. S.; Drevets, W. C. Reward processing after catecholamine depletion in unmedicated, remitted subjects with major depressive disorder. Biol. Psychiatry 2009, 66, 201−205. 2161



Perspective

(44) Homan, P.; Neumeister, A.; Nugent, A. C.; Charney, D. S.; Drevets, W. C.; Hasler, G. Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression. Transl. Psychiatry 2015, 5, e532. (45) Baumeister, A. A.; Hawkins, M. F.; Uzelac, S. M. The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis. J. Hist. Neurosci. 2003, 12, 207−220. (46) Zajecka, J. M.; Zajecka, A. M. A clinical overview of monoamine oxidase inhibitors: pharmacological profile, efficacy, safety/tolerability, and strategies for successful outcomes in the management of major depressive disorders. Psychiatr. Ann. 2014, 44, 513−523. (47) Shulman, K. I.; Herrmann, N.; Walker, S. E. Current place of monoamine oxidase inhibitors in the treatment of depression. CNS Drugs 2013, 27, 789−797. (48) Cooper, J. A.; Tucker, V. L.; Papakostas, G. I. Resolution of sleepiness and fatigue: a comparison of bupropion and selective serotonin reuptake inhibitors in subjects with major depressive disorder achieving remission at doses approved in the European Union. J. Psychopharmacol. (London, U. K.) 2014, 28, 118−124. (49) Hori, H.; Kunugi, H. Dopamine agonist-responsive depression. Psychogeriatrics 2013, 13, 189−195. (50) Pae, C.-U. Pramipexole augmentation in treatment-resistant major depressive disorder. Expert Rev. Neurother. 2014, 14, 5−8. (51) Zhou, X.; Keitner, G. I.; Qin, B.; Ravindran, A. V.; Bauer, M.; Del Giovane, C.; Zhao, J.; Liu, Y.; Fang, Y.; Zhang, Y.; Xie, P. Atypical antipsychotic augmentation for treatment-resistant depression: a systematic review and network meta-analysis. Int. J. Neuropsychopharmacol. 2015, 18, pyv060. (52) de Bartolomeis, A.; Tomasetti, C.; Iasevoli, F. Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism. CNS Drugs 2015, 29, 773−799. (53) Blier, P.; El Mansari, M. Serotonin and beyond: therapeutics for major depression. Philos. Trans. R. Soc., B 2013, 368, 20120536. (54) Comley, R. A.; Salinas, C. A.; Slifstein, M.; Petrone, M.; Marzano, C.; Bennacef, I.; Shotbolt, P.; Van der Aart, J.; Neve, M.; Iavarone, L.; Gomeni, R.; Laruelle, M.; Gray, F. A.; Gunn, R. N.; Rabiner, E. A. Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography. J. Pharmacol. Exp. Ther. 2013, 346, 311−317. (55) Antidepressant; Wikipedia, 2017; https://en.wikipedia.org/wiki/ Antidepressant (accessed May 29, 2017). (56) Koblan, K. S.; Hopkins, S. C.; Sarma, K.; Jin, F.; Goldman, R.; Kollins, S. H.; Loebel, A. Dasotraline for the treatment of attentiondeficit/hyperactivity disorder: a randomized, double-blind, placebocontrolled, proof-of-concept trial in adults. Neuropsychopharmacology 2015, 40, 2745−2752. (57) Bymaster, F. P.; Golembiowska, K.; Kowalska, M.; Choi, Y. K.; Tarazi, F. I. Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB-1020: implications for treatment of attention-deficit hyperactivity disorder. Synapse 2012, 66, 522−532. (58) Neurovance Announces Positive Centanafadine Phase 2b Results for Adult ADHD, and Plans for Phase 3 Trials; Neurovance, Inc.: Cambridge, MA, July 27, 2016; http://www.neurovance.com/wpcontent/uploads/2016/07/Press_Release-Neurovance_CTN_ 072716_Final_en.pdf (accessed May 29, 2017). (59) Wilens, T. E.; Klint, T.; Adler, L.; West, S.; Wesnes, K.; Graff, O.; Mikkelsen, B. A randomized controlled trial of a novel mixed monoamine reuptake inhibitor in adults with ADHD. Behav. Brain Funct. 2008, 4, 24. (60) Sunovion Announces Results from Pivotal Study Evaluating Novel Drug Candidate Dasotraline in Children with ADHD; Sunovion Pharmaceuticals: Marlborough, MA, September 20, 2016; http:// www.sunovion.us/featured-news/press-releases/20160920.pdf (accessed May 29, 2017). (61) Hache, G.; Coudore, F.; Gardier, A. M.; Guiard, B. P. Monoaminergic antidepressants in the relief of pain: potential therapeutic utility of triple reuptake inhibitors (TRIs). Pharmaceuticals 2011, 4, 285−342.

(62) Hache, G.; Guiard, B. P.; Nguyen, T. H.; Quesseveur, G.; Gardier, A. M.; Peters, D.; Munro, G.; Coudore, F. Antinociceptive activity of the new triple reuptake inhibitor NS18283 in a mouse model of chemotherapy-induced neuropathic pain. Eur. J. Pain 2015, 19, 322−333. (63) Rosenberg, M. B.; Carroll, F. I.; Negus, S. S. Effects of monoamine reuptake inhibitors in assays of acute pain-stimulated and pain-depressed behavior in rats. J. Pain 2013, 14, 246−259. (64) Krieter, P. A.; Gohdes, M.; Musick, T. J.; Duncanson, F. P.; Bridson, W. E. Pharmacokinetics, disposition, and metabolism of bicifadine in humans. Drug Metab. Dispos. 2008, 36, 252−259. (65) NS2359 for Treatment of Cocaine Addiction; Saniona: Ballerup, Denmark, 2017; http://saniona.com/pipeline/ns2359/ (accessed May 29, 2017). (66) Levin, E. D.; Wells, C.; Johnson, J. E.; Rezvani, A. H.; Bymaster, F. P.; Rose, J. E. Amitifadine, a triple monoamine re-uptake inhibitor, reduces nicotine self-administration in female rats. Eur. J. Pharmacol. 2015, 764, 30−37. (67) O’Tousa, D. S.; Warnock, K. T.; Matson, L. M.; Namjoshi, O. A.; Linn, M. V.; Tiruveedhula, V. V.; Halcomb, M. E.; Cook, J.; Grahame, N. J.; June, H. L. Triple monoamine uptake inhibitors demonstrate a pharmacologic association between excessive drinking and impulsivity in high-alcohol-preferring (HAP) mice. Addict. Biol. 2015, 20, 236−247. (68) Appel, L.; Bergstrom, M.; Buus Lassen, J.; Langstrom, B. Tesofensine, a novel triple monoamine re-uptake inhibitor with antiobesity effects: dopamine transporter occupancy as measured by PET. Eur. Neuropsychopharmacol. 2014, 24, 251−261. (69) DOV 21,947 Demonstrates Significant Body Weight and BMI Reductions in Drug-Compliant Subjects in Phase Ib Clinical Study; DOV Pharmaceutical: Somerset, NJ, September 25, 2007; https://www.sec. gov/Archives/edgar/data/1066833/000114420407051174/v088668_ ex99-1.htm (accessed May 29, 2017). (70) Astrup, A.; Meier, D. H.; Mikkelsen, B. O.; Villumsen, J. S.; Larsen, T. M. Weight loss produced by tesofensine in patients with Parkinson’s or Alzheimer’s disease. Obesity 2008, 16, 1363−1369. (71) Tesomet for Treatment of Type 2 Diabetes; Saniona: Ballerup, Denmark, 2017; http://saniona.com/pipeline/tesomet-t2d/ (accessed May 29, 2017). (72) Li, Y. W.; Langdon, S.; Pieschl, R.; Strong, T.; Wright, R. N.; Rohrbach, K.; Lelas, S.; Lodge, N. J. Monoamine reuptake site occupancy of sibutramine: relationship to antidepressant-like and thermogenic effects in rats. Eur. J. Pharmacol. 2014, 737, 47−56. (73) Meridia (Sibutramine Hydrochloride Monohydrate) Capsules CSIV; Abbott Laboratories: North Chicago, IL, 2017; http://www.fda. gov/downloads/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ UCM130745.pdf (accessed May 29, 2017). (74) Our Pipeline: We’re Focused on the Innovative Application of Science and Medicine; Sunovion: Marlborough, MA, 2017; http://www. sunovion.us/research-and-development/pipeline.html (accessed May 29, 2017). (75) Cortellis; Clarivate Analytics: Philadelphia, 2017; https:// cortellis.thomsonreuterslifesciences.com/ (accessed May 29, 2017). (76) Hansen, H. H.; Hansen, G.; Tang-Christensen, M.; Larsen, P. J.; Axel, A. M.; Raben, A.; Mikkelsen, J. D. The novel triple monoamine reuptake inhibitor tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant. Eur. J. Pharmacol. 2010, 636, 88−95. (77) Rascol, O.; Poewe, W.; Lees, A.; Aristin, M.; Salin, L.; Juhel, N.; Waldhauser, L.; Schindler, T.; ADVANS Study Group. Tesofensine (NS 2330), a monoamine reuptake inhibitor, in patients with advanced Parkinson disease and motor fluctuations: the ADVANS Study. Arch. Neurol. 2008, 65, 577−583. (78) Schroeder, C.; Jordan, J. Norepinephrine transporter function and human cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 2012, 303, H1273−1282. (79) DeLorenzo, C.; Lichenstein, S.; Schaefer, K.; Dunn, J.; Marshall, R.; Organisak, L.; Kharidia, J.; Robertson, B.; Mann, J. J.; Parsey, R. V. 2162



Perspective

(93) DOV Pharmaceutical; Wikipedia, 2017; https://en.wikipedia. org/wiki/DOV_Pharmaceutical (accessed May 29, 2017). (94) Amitifadine; Euthymics Bioscience: Cambridge, MA, 2017; http://euthymics.com/amitifadine/ (accessed May 29, 2017). (95) Tesofensine Monotherapy for Treatment of Obesity; Saniona: Ballerup, Denmark, 2017; http://saniona.com/pipeline/tesofensine/ (accessed May 29, 2017). (96) Completion of Phase 1 Clinical Studies of Ansofaxine Hydrochloride Extended Release Tablets (LY03005) in the U.S.; Luye Pharma: Shanghai, August 13, 2015; http://www.luye.cn/lvye_en/newsshow. php?id=138 (accessed May 29, 2017). (97) Epstein, J. W.; Brabander, H. J.; Fanshawe, W. J.; Hofmann, C. M.; McKenzie, T. C.; Safir, S. R.; Osterberg, A. C.; Cosulich, D. B.; Lovell, F. M. 1-Aryl-3-azabicyclo[3.1.0]hexanes, a new series of nonnarcotic analgesic agents. J. Med. Chem. 1981, 24, 481−490. (98) Epstein, J. W.; Osterberg, A. C.; Brabander, H. J. Treating Depression Using Azabicyclohexanes. US4435419A, 1984. (99) Skolnick, P.; Krieter, P.; Tizzano, J.; Basile, A.; Popik, P.; Czobor, P.; Lippa, A. Preclinical and clinical pharmacology of DOV 216,303, a ″triple″ reuptake inhibitor. CNS Drug Rev. 2006, 12, 123− 134. (100) Prins, J.; Kenny, P. J.; Doomernik, I.; Schreiber, R.; Olivier, B.; Mechiel Korte, S. The triple reuptake inhibitor DOV 216,303 induces long-lasting enhancement of brain reward activity as measured by intracranial self-stimulation in rats. Eur. J. Pharmacol. 2012, 693, 51− 56. (101) Paterson, N. E.; Balci, F.; Campbell, U.; Olivier, B. E.; Hanania, T. The triple reuptake inhibitor DOV216,303 exhibits limited antidepressant-like properties in the differential reinforcement of low-rate 72-second responding assay, likely due to dopamine reuptake inhibition. J. Psychopharmacol. 2011, 25, 1357−1364. (102) Popik, P.; Krawczyk, M.; Golembiowska, K.; Nowak, G.; Janowsky, A.; Skolnick, P.; Lippa, A.; Basile, A. S. Pharmacological profile of the ″triple″ monoamine neurotransmitter uptake inhibitor, DOV 102,677. Cell. Mol. Neurobiol. 2006, 26, 855−871. (103) McMillen, B. A.; Shank, J. E.; Jordan, K. B.; Williams, H. L.; Basile, A. S. Effect of DOV 102,677 on the volitional consumption of ethanol by Myers’ high ethanol-preferring rat. Alcohol.: Clin. Exp. Res. 2007, 31, 1866−1871. (104) Yang, A. R.; Yi, H. S.; Warnock, K. T.; Mamczarz, J.; June, H. L., Jr.; Mallick, N.; Krieter, P. A.; Tonelli, L.; Skolnick, P.; Basile, A. S.; June, H. L., Sr. Effects of the triple monoamine uptake inhibitor DOV 102,677 on alcohol-motivated responding and antidepressant activity in alcohol-preferring (P) rats. Alcohol.: Clin. Exp. Res. 2012, 36, 863− 873. (105) Bymaster, F. P.; Chao, P.; Schulze, H.; Tran, P. V.; Marshall, R. D. Biopharmaceutical characterization, metabolism, and brain penetration of the triple reuptake inhibitor amitifadine. Drug Metab. Lett. 2013, 7, 23−33. (106) Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.; Lippa, A. S. Antidepressant-like actions of DOV 21,947: a ″triple″ reuptake inhibitor. Eur. J. Pharmacol. 2003, 461, 99−104. (107) Warnock, K. T.; Yang, A. R.; Yi, H. S.; June, H. L., Jr.; Kelly, T.; Basile, A. S.; Skolnick, P.; June, H. L. Amitifadine, a triple monoamine uptake inhibitor, reduces binge drinking and negative affect in an animal model of co-occurring alcoholism and depression symptomatology. Pharmacol., Biochem. Behav. 2012, 103, 111−118. (108) Tizzano, J. P.; Stribling, D. S.; Perez-Tilve, D.; Strack, A.; Frassetto, A.; Chen, R. Z.; Fong, T. M.; Shearman, L.; Krieter, P. A.; Tschop, M. H.; Skolnick, P.; Basile, A. S. The triple uptake inhibitor (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] hexane hydrochloride (DOV 21947) reduces body weight and plasma triglycerides in rodent models of diet-induced obesity. J. Pharmacol. Exp. Ther. 2008, 324, 1111−1126. (109) Tran, P.; Skolnick, P.; Czobor, P.; Huang, N. Y.; Bradshaw, M.; McKinney, A.; Fava, M. Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. J. Psychiatr. Res. 2012, 46, 64−71.

SEP-225289 serotonin and dopamine transporter occupancy: a PET study. J. Nucl. Med. 2011, 52, 1150−1155. (80) Sramek, J. J.; Hardy, L. W.; Bieck, P.; Zamora, C.; Versavel, M.; Kharidia, J.; Grinnell, T.; Chen, Y. L.; Sullivan, M.; Ding, H.; Cutler, N. R. Exploratory biomarker study of the triple reuptake inhibitor SEP432 compared to the dual reuptake inhibitor duloxetine in healthy normal subjects. CNS Neurosci. Ther. 2016, 22, 404−412. (81) Takano, H.; Arakawa, R.; Nogami, T.; Suzuki, M.; Nagashima, T.; Fujiwara, H.; Kimura, Y.; Kodaka, F.; Takahata, K.; Shimada, H.; Murakami, Y.; Tateno, A.; Yamada, M.; Ito, H.; Kawamura, K.; Zhang, M.-R.; Takahashi, H.; Kato, M.; Okubo, Y.; Suhara, T. Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[18F]FMeNER-D2. Int. J. Neuropsychopharmacol. 2014, 17, 553−560. (82) Muller, P. Y.; Milton, M. N. The determination and interpretation of the therapeutic index in drug development. Nat. Rev. Drug Discovery 2012, 11, 751−761. (83) Sorensen, G.; Husum, H.; Brennum, L. T.; Bundgaard, C.; Montezinho, L. C. P.; Mork, A.; Woertwein, G.; Woldbye, D. P. D. Addiction-related effects of DOV 216,303 and cocaine: a comparative study in the mouse. Basic Clin. Pharmacol. Toxicol. 2014, 114, 451− 459. (84) Volkow, N. D.; Fowler, J. S.; Wang, G. J.; Swanson, J. M. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol. Psychiatry 2004, 9, 557−569. (85) Liang, Y.; Shaw, A. M.; Boules, M.; Briody, S.; Robinson, J.; Oliveros, A.; Blazar, E.; Williams, K.; Zhang, Y.; Carlier, P. R.; Richelson, E. Antidepressant-like pharmacological profile of a novel triple reuptake inhibitor, (1S,2S)-3-(methylamino)-2-(naphthalen-2yl)-1-phenylpropan-1-ol (PRC200-SS). J. Pharmacol. Exp. Ther. 2008, 327, 573−583. (86) Koblan, K. S.; Hopkins, S. C.; Sarma, K.; Gallina, N.; Jin, F.; Levy-Cooperman, N.; Schoedel, K. A.; Loebel, A. Assessment of human abuse potential of dasotraline compared to methylphenidate and placebo in recreational stimulant users. Drug Alcohol Depend. 2016, 159, 26−34. (87) Schoedel, K. A.; Meier, D.; Chakraborty, B.; Manniche, P. M.; Sellers, E. M. Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users. Clin. Pharmacol. Ther. 2010, 88, 69−78. (88) Neurovance Announces Top-Line Study Results Suggest Lower Abuse Potential for Centanafadine Compared to Stimulants Used for Adult ADHD; Neurovance: Cambridge, MA, 2014; http://www.neurovance. com/wp-content/uploads/2014/08/Press-Release_-Neurovance_ HAL-results.-BWire-FINAL.pdf (accessed May 29, 2017). (89) Lengyel, K.; Pieschl, R.; Strong, T.; Molski, T.; Mattson, G.; Lodge, N. J.; Li, Y. W. Ex vivo assessment of binding site occupancy of monoamine reuptake inhibitors: methodology and biological significance. Neuropharmacology 2008, 55, 63−70. (90) Micheli, F.; Cavanni, P.; Arban, R.; Benedetti, R.; Bertani, B.; Bettati, M.; Bettelini, L.; Bonanomi, G.; Braggio, S.; Checchia, A.; Davalli, S.; Di Fabio, R.; Fazzolari, E.; Fontana, S.; Marchioro, C.; Minick, D.; Negri, M.; Oliosi, B.; Read, K. D.; Sartori, I.; Tedesco, G.; Tarsi, L.; Terreni, S.; Visentini, F.; Zocchi, A.; Zonzini, L. 1-(Aryl)-6[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]3-azabicyclo[3.1.0]hexanes: a new series of potent and selective triple reuptake inhibitors. J. Med. Chem. 2010, 53, 2534−2551. (91) Micheli, F.; Cavanni, P.; Andreotti, D.; Arban, R.; Benedetti, R.; Bertani, B.; Bettati, M.; Bettelini, L.; Bonanomi, G.; Braggio, S.; Carletti, R.; Checchia, A.; Corsi, M.; Fazzolari, E.; Fontana, S.; Marchioro, C.; Merlo-Pich, E.; Negri, M.; Oliosi, B.; Ratti, E.; Read, K. D.; Roscic, M.; Sartori, I.; Spada, S.; Tedesco, G.; Tarsi, L.; Terreni, S.; Visentini, F.; Zocchi, A.; Zonzini, L.; Di Fabio, R. 6-(3,4dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: a new potent and selective triple reuptake inhibitor. J. Med. Chem. 2010, 53, 4989−5001. (92) Shao, L.; Li, W.; Xie, Q.; Yin, H. Triple reuptake inhibitors: a patent review (2006 - 2012). Expert Opin. Ther. Pat. 2014, 24, 131− 154. 2163



Perspective

(110) Euthymics Reports Top-Line Results from Triade Trial of Amitifadine for Major Depressive Disorder; Euthymics Bioscience: Cambridge, MA, May 29, 2013; http://euthymics.com/wp-content/ uploads/2013/05/FINAL_Euthymics_TRIADE_Results_052913.pdf (accessed May 29, 2017). (111) Lehr, T.; Staab, A.; Tillmann, C.; Trommeshauser, D.; Raschig, A.; Schaefer, H. G.; Kloft, C. Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer’s disease. Br. J. Clin. Pharmacol. 2007, 64, 36−48. (112) Sjodin, A.; Gasteyger, C.; Nielsen, A. L.; Raben, A.; Mikkelsen, J. D.; Jensen, J. K.; Meier, D.; Astrup, A. The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men. Int. J. Obes. 2010, 34, 1634−1643. (113) Bentzen, B. H.; Grunnet, M.; Hyveled-Nielsen, L.; Sundgreen, C.; Lassen, J. B.; Hansen, H. H. Anti-hypertensive treatment preserves appetite suppression while preventing cardiovascular adverse effects of tesofensine in rats. Obesity 2013, 21, 985−992. (114) Learned, S.; Graff, O.; Roychowdhury, S.; Moate, R.; Krishnan, K. R.; Archer, G.; Modell, J. G.; Alexander, R.; Zamuner, S.; Lavergne, A.; Evoniuk, G.; Ratti, E. Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials. J. Psychopharmacol. 2012, 26, 653−662. (115) Peters, D.; Nielsen, E. O.; Nielsen, K. S.; Munro, G. Chromen2-one Derivatives of Tropine, and Their Preparation and Use as Monoamine Neurotransmitter Re-uptake Inhibitors. WO2010130620A1, 2010. (116) Jerussi, T. P.; Fang, Q. K.; Currie, M. Preparation of trans-4(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine for Treatment of CNS Disorders. WO2004024669A1, 2004. (117) Shao, L.; Wang, F.; Malcolm, S. C.; Ma, J.; Hewitt, M. C.; Campbell, U. C.; Bush, L. R.; Spicer, N. A.; Engel, S. R.; Saraswat, L. D.; Hardy, L. W.; Koch, P.; Schreiber, R.; Spear, K. L.; Varney, M. A. Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors. Bioorg. Med. Chem. 2011, 19, 663−676. (118) Shao, L.; Hewitt, M. C.; Malcolm, S. C.; Wang, F.; Ma, J.; Campbell, U. C.; Spicer, N. A.; Engel, S. R.; Hardy, L. W.; Jiang, Z. D.; Schreiber, R.; Spear, K. L.; Varney, M. A. Synthesis and pharmacological characterization of bicyclic triple reuptake inhibitor 3-aryl octahydrocyclopenta[c]pyrrole analogues. J. Med. Chem. 2011, 54, 5283−5295. (119) Shao, L.; Hewitt, M. C.; Wang, F.; Malcolm, S. C.; Ma, J.; Campbell, J. E.; Campbell, U. C.; Engel, S. R.; Spicer, N. A.; Hardy, L. W.; Schreiber, R.; Spear, K. L.; Varney, M. A. Discovery of N-methyl1-(1-phenylcyclohexyl)ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor. Bioorg. Med. Chem. Lett. 2011, 21, 1434−1437. (120) Shao, L.; Wang, F.; Malcolm, S. C.; Hewitt, M. C.; Bush, L. R.; Ma, J.; Varney, M. A.; Campbell, U.; Engel, S. R.; Hardy, L. W.; Koch, P.; Campbell, J. E. Cycloalkylamines as Monoamine Reuptake Inhibitors and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of nervous system agents. WO2007081857A2, 2007. (121) Comley, R. A.; Salinas, C. A.; Slifstein, M.; Petrone, M.; Marzano, C.; Bennacef, I.; Shotbolt, P.; Van der Aart, J.; Neve, M.; Iavarone, L.; Gomeni, R.; Laruelle, M.; Gray, F. A.; Gunn, R. N.; Rabiner, E. A. Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography. J. Pharmacol. Exp. Ther. 2013, 346, 311−317. (122) Micheli, F.; Cavanni, P.; Bettati, M.; Bonanomi, G.; Di Fabio, R.; Fazzolari, E.; Marchioro, C.; Roscic, M.; Tarsi, L.; Visentini, F.; Zonzini, L.; Worby, A. 1-Heteroaryl-6-(3,4-dichlorophenyl)-3azabicyclo[4.1.0]heptane: further insights into a class of triple reuptake inhibitors. Bioorg. Med. Chem. 2011, 19, 3451−3461. (123) Profeta, R.; Klein, J.; Spada, S.; Ferroni, F.; Paio, A.; Andreotti, D. Synthesis of 5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2azabicyclo[3.2.1]octane derivatives as constrained aryl-piperidines

with activity as triple re-uptake inhibitors. Tetrahedron Lett. 2010, 51, 5521−5524. (124) Bettati, M.; Cavanni, P.; Di Fabio, R.; Oliosi, B.; Perini, O.; Scheid, G.; Tedesco, G.; Zonzini, L.; Micheli, F. Oxa-azaspiro derivatives: a novel class of triple re-uptake inhibitors. ChemMedChem 2010, 5, 361−366. (125) Liu, S.; Zha, C.; Nacro, K.; Hu, M.; Cui, W.; Yang, Y. L.; Bhatt, U.; Sambandam, A.; Isherwood, M.; Yet, L.; Herr, M. T.; Ebeltoft, S.; Hassler, C.; Fleming, L.; Pechulis, A. D.; Payen-Fornicola, A.; Holman, N.; Milanowski, D.; Cotterill, I.; Mozhaev, V.; Khmelnitsky, Y.; Guzzo, P. R.; Sargent, B. J.; Molino, B. F.; Olson, R.; King, D.; Lelas, S.; Li, Y. W.; Johnson, K.; Molski, T.; Orie, A.; Ng, A.; Haskell, R.; Clarke, W.; Bertekap, R.; O’Connell, J.; Lodge, N.; Sinz, M.; Adams, S.; Zaczek, R.; Macor, J. E. Design and synthesis of 4-heteroaryl 1,2,3,4tetrahydroisoquinolines as triple reuptake inhibitors. ACS Med. Chem. Lett. 2014, 5, 760−765. (126) Bhagwagar, Z.; Torbeyns, A.; Hennicken, D.; Zheng, M.; Dunlop, B. W.; Mathew, S. J.; Khan, A.; Weisler, R.; Nelson, C.; Shelton, R.; Thase, M. E.; Lane, R. Assessment of the efficacy and safety of BMS-820836 in patients with treatment-resistant major depression: results from 2 randomized, double-blind studies. J. Clin. Psychopharmacol. 2015, 35, 454−459. (127) Risinger, R.; Bhagwagar, Z.; Luo, F.; Cahir, M.; Miler, L.; Mendonza, A. E.; Meyer, J. H.; Zheng, M.; Hayes, W. Evaluation of safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-820836 in healthy subjects: a placebo-controlled, ascending single-dose study. Psychopharmacology (Berl.) 2014, 231, 2299−2310. (128) Carlier, P. R.; Richelson, E. Preparation of N,N-Dimethyl-3cyclohexyl-3-hydroxy-2-(2-naphthyl)propylamines as Neurotransmitter Reuptake Inhibitors. WO2005120200A2, 2005. (129) Shaw, A. M.; Boules, M.; Zhang, Y.; Williams, K.; Robinson, J.; Carlier, P. R.; Richelson, E. Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050. Eur. J. Pharmacol. 2007, 555, 30−36. (130) Guha, M.; Heier, A.; Price, S.; Bielenstein, M.; Caccese, R. G.; Heathcote, D. I.; Simpson, T. R.; Stong, D. B.; Bodes, E. Assessment of biomarkers of drug-induced kidney injury in cynomolgus monkeys treated with a triple reuptake inhibitor. Toxicol. Sci. 2011, 120, 269− 283. (131) Bannwart, L. M.; Carter, D. S.; Cai, H.-Y.; Choy, J. C.; Greenhouse, R.; Jaime-Figueroa, S.; Iyer, P. S.; Lin, C. J.; Lee, E. K.; Lucas, M. C.; Lynch, S. M.; Madera, A. M.; Moore, A.; Ozboya, K.; Raptova, L.; Roetz, R.; Schoenfeld, R. C.; Stein, K. A.; Steiner, S.; Villa, M.; Weikert, R. J.; Zhai, Y. Novel 3,3-disubstituted pyrrolidines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 6062−6066. (132) Lucas, M. C.; Weikert, R. J.; Carter, D. S.; Cai, H.-Y.; Greenhouse, R.; Iyer, P. S.; Lin, C. J.; Lee, E. K.; Madera, A. M.; Moore, A.; Ozboya, K.; Schoenfeld, R. C.; Steiner, S.; Zhai, Y.; Lynch, S. M. Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain. Bioorg. Med. Chem. Lett. 2010, 20, 5559−5566. (133) Lucas, M. C.; Carter, D. S.; Cai, H.-Y.; Lee, E. K.; Schoenfeld, R. C.; Steiner, S.; Villa, M.; Weikert, R. J.; Iyer, P. S. Novel, achiral aminoheterocycles as selective monoamine reuptake inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 4630−4633. (134) Carter, D. S.; Cai, H.-Y.; Lee, E. K.; Iyer, P. S.; Lucas, M. C.; Roetz, R.; Schoenfeld, R. C.; Weikert, R. J. 2-Substituted N-aryl piperazines as novel triple reuptake inhibitors for the treatment of depression. Bioorg. Med. Chem. Lett. 2010, 20, 3941−3945. (135) Honda, E.; Ishichi, Y.; Kimura, E.; Yoshikawa, M.; Kanzaki, N.; Nakagawa, H.; Terao, Y.; Suzuki, A.; Kawai, T.; Arakawa, Y.; Ohta, H.; Terauchi, J. Design, synthesis, and biological activities of 1-aryl-1,4diazepan-2-one derivatives as novel triple reuptake inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 3898−3902. (136) Ishichi, Y.; Kimura, E.; Honda, E.; Yoshikawa, M.; Nakahata, T.; Terao, Y.; Suzuki, A.; Kawai, T.; Arakawa, Y.; Ohta, H.; Kanzaki, N.; Nakagawa, H.; Terauchi, J. Novel triple reuptake inhibitors with low risk of CAD associated liabilities: design, synthesis and biological 2164



Perspective

activities of 4-[(1S)-1-(3,4-dichlorophenyl)-2-methoxyethyl]piperidine and related compounds. Bioorg. Med. Chem. 2013, 21, 4600−4613. (137) Hou, J.; Xing, Y.; Zuo, D.; Wu, Y.; Tian, J.; Meng, Q.; Yang, M. In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor. Physiol. Behav. 2015, 138, 141−149. (138) Zhang, R.; Li, X.; Shi, Y.; Shao, Y.; Sun, K.; Wang, A.; Sun, F.; Liu, W.; Wang, D.; Jin, J.; Li, Y. The effects of LPM570065, a novel triple reuptake inhibitor, on extracellular serotonin, dopamine and norepinephrine levels in rats. PLoS One 2014, 9, e91775. (139) Sharma, H.; Santra, S.; Debnath, J.; Antonio, T.; Reith, M.; Dutta, A. Flexible and biomimetic analogs of triple uptake inhibitor 4((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: Synthesis, biological characterization, and development of a pharmacophore model. Bioorg. Med. Chem. 2014, 22, 311−324. (140) Sharma, H.; Santra, S.; Dutta, A. Triple reuptake inhibitors as potential next-generation antidepressants: a new hope? Future Med. Chem. 2015, 7, 2385−2406. (141) Zhang, S.; Zhen, J.; Reith, M. E.; Dutta, A. K. Discovery of novel trisubstituted asymmetric derivatives of (2S,4R,5R)-2-benzhydryl-5-benzylaminotetrahydropyran-4-ol, exhibiting high affinity for serotonin and norepinephrine transporters in a stereospecific manner. J. Med. Chem. 2005, 48, 4962−4971. (142) Dutta, A. K.; Gopishetty, B.; Gogoi, S.; Ali, S.; Zhen, J.; Reith, M. The novel trisubstituted pyran derivative D-142 has triple monoamine reuptake inhibitory activity and exerts potent antidepressant-like activity in rodents. Eur. J. Pharmacol. 2011, 671, 39− 44. (143) Dutta, A. K.; Santra, S.; Sharma, H.; Voshavar, C.; Xu, L.; Mabrouk, O.; Antonio, T.; Reith, M. E. A. Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters. PLoS One 2014, 9, e113420. (144) Wayne State University Technology Enters Exclusive License Agreement with TRImaran Pharma Inc. to Develop New Class of Drugs; Wayne State University: Detroit, MI, February 6, 2016; http://www. trimaranpharmainc.com/news.html (accessed May 29, 2017). (145) Maryanoff, B. E.; McComsey, D. F.; Costanzo, M. J.; Setler, P. E.; Gardocki, J. F.; Shank, R. P.; Schneider, C. R. Pyrroloisoquinoline antidepressants. potent, enantioselective inhibition of tetrabenazineinduced ptosis and neuronal uptake of norepinephrine, dopamine, and serotonin. J. Med. Chem. 1984, 27, 943−946. (146) Maryanoff, B. E.; McComsey, D. F.; Gardocki, J. F.; Shank, R. P.; Costanzo, M. J.; Nortey, S. O.; Schneider, C. R.; Setler, P. E. Pyrroloisoquinoline antidepressants. 2. in-depth exploration of structure-activity relationships. J. Med. Chem. 1987, 30, 1433−1454. (147) Aluisio, L.; Lord, B.; Barbier, A. J.; Fraser, I. C.; Wilson, S. J.; Boggs, J.; Dvorak, L. K.; Letavic, M. A.; Maryanoff, B. E.; Carruthers, N. I.; Bonaventure, P.; Lovenberg, T. W. In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor. Eur. J. Pharmacol. 2008, 587, 141−146. (148) Roggen, H.; Kehler, J.; Stensbol, T. B.; Hansen, T. Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters. Bioorg. Med. Chem. Lett. 2007, 17, 2834−2837. (149) Axford, L.; Boot, J. R.; Hotten, T. M.; Keenan, M.; Martin, F. M.; Milutinovic, S.; Moore, N. A.; O’Neill, M. F.; Pullar, I. A.; Tupper, D. E.; Van Belle, K. R.; Vivien, V. Bicyclo[2.2.1]heptanes as novel triple re-uptake inhibitors for the treatment of depression. Bioorg. Med. Chem. Lett. 2003, 13, 3277−3280. (150) Caldarone, B. J.; Paterson, N. E.; Zhou, J.; Brunner, D.; Kozikowski, A. P.; Westphal, K. G.; Korte-Bouws, G. A.; Prins, J.; Korte, S. M.; Olivier, B.; Ghavami, A. The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties. J. Pharmacol. Exp. Ther. 2010, 335, 762−770. (151) Zhou, J.; He, R.; Johnson, K. M.; Ye, Y.; Kozikowski, A. P. Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization. J. Med. Chem. 2004, 47, 5821−5824.

(152) Han, Y.; Han, M.; Shin, D.; Song, C.; Hahn, H.-G. Exploration of novel 3-substituted azetidine derivatives as triple reuptake inhibitors. J. Med. Chem. 2012, 55, 8188−8192. (153) Yun, J.; Han, M.; Song, C.; Cheon, S. H.; Choi, K.; Hahn, H. G. Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 3234−3237. (154) Han, M.; Song, C.; Jeong, N.; Hahn, H. G. Exploration of 3aminoazetidines as triple reuptake inhibitors by bioisosteric modification of 3-alpha-oxyazetidine. ACS Med. Chem. Lett. 2014, 5, 999−1004. (155) Weng, Z.; Li, J. Synthesis and antidepressant activity of optical isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl) propan-1-ol (SIPI5056). Bioorg. Med. Chem. Lett. 2010, 20, 1256−1259. (156) Zheng, Y. Y.; Guo, L.; Zhen, X. C.; Li, J. Q. Synthesis and antidepressant activity of arylalkanol-piperidine derivatives as triple reuptake inhibitors. Eur. J. Med. Chem. 2012, 54, 123−136. (157) Zheng, Y. Y.; Weng, Z. J.; Xie, P.; Zhu, M. Y.; Xing, L. X.; Li, J. Q. Synthesis and pharmacological investigation of aralkyl diamine derivatives as potential triple reuptake inhibitors. Eur. J. Med. Chem. 2014, 86, 219−234. (158) McKinney, A.; Bymaster, F. Methods for Inhibiting Native and Promiscuous Uptake of Monoamine Neurotransmitters Using a Triple Reuptake Inhibitor. US20140228421A1, 2014. (159) Pankevich, D. E.; Altevogt, B. M.; Dunlop, J.; Gage, F. H.; Hyman, S. E. Improving and accelerating drug development for nervous system disorders. Neuron 2014, 84, 546−553.

2165


Triple Reuptake Inhibitors as Potential ... - ACS Publications

Recommend Documents