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Perspective

The Return of D4 Dopamine Receptor Antagonists in Drug Discovery Craig W Lindsley, and Corey R. Hopkins J. Med. Chem., Just Accepted Manuscript • Publication Date (Web): 10 May 2017 Downloaded from http://pubs.acs.org on May 11, 2017

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Journal of Medicinal Chemistry

The Return of D4 Dopamine Receptor Antagonists in Drug Discovery Craig W. Lindsley1,2,3,4* and Corey R. Hopkins5*

1

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232

2

Department of Chemistry, Vanderbilt University, Nashville, TN 37232

3

Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN

37232 4

Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232

5

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE

68198-6125

Keywords: G Protein-Coupled Receptor, Seven Transmembrane Receptor, dopamine, dopamine receptor subtype 4 (D4), schizophrenia, Parkinson’s disease (PD), L-745,870

ABSTRACT: The dopamine D4 receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D4, relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine.

Unfortunately, D4 antagonists that were developed for

Schizophrenia, failed in the clinic. Thus, D4 fell out of favor as a therapeutic target, and work in this area was silent for decades. Recently, D4 ligands with improved selectivity for D4 against

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not only D1-3,5, but also other biogenic amine targets, have emerged, and D4 is once again in the spotlight as a novel target for both addiction and Parkinson’s disease (PD), as well as other emerging diseases. This Perspective will review the historical data for D4, review the known D4 ligands, and then highlight new data supporting a role for D4 inhibition in addiction, PD and cancer.

1. INTRODUCTION

1.1

Dopamine receptors. As there are over 50 years of excellent reviews on different

aspects of dopamine receptors,1-4 we will provide a brief overview to set the stage for the readers unfamiliar with the topic. Dopamine (1), a catecholamine neurotransmitter, is a predominant neurotransmitter in the mammalian CNS and periphery with a myriad of physiological functions including movement, emotion, cognition, food intake, reinforcement/reward, cardiovascular function, hormone secretion and renal function to list but a few.1-4

After dopamine was

recognized as a neurotransmitter in the 1950s,5 Cools and van Rossum rationalized that there must be multiple dopamine receptors (DRs) to facilitate the broad actions of 1 in the periphery and CNS.6 Employing biochemical methods, Spano7 and Kebabian8 identified two DRs, both G protein-coupled receptors (GPCRs) or Seven Transmembrane Receptors (7-TMRs), coined D1like and D2-like receptors. D1-like receptors stimulate adenyl cyclase (AC) and phospholipase C through Gαs to increase cAMP (Figure 1). D2-like receptors inhibit AC through Gαi/o to not only decrease cAMP, but also stimulate glycogen synthase kinse 3β (GSK-3β) and potassium channels, while inhibiting calcium currents.1-4,6-8

In the 1980s and 1990s, gene cloning

technology found five distinct DRs, named D1-D5, which were divided into two families: D1-like


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(D1 and D5) and D2-like (D2, D3 and D4).1-4,6-9 D1 and D5 are characterized as having short intracellular loop 3 (i3) and long terminal carboxy tails; in contrast, D2, D3 and D4 possess long i3s and short terminal carboxy tails.1-4,6-9 The i3 loop is key for interaction of the DR with the G protein, and the genes of the D2-like receptors possess significant polymorphisms in this region. For example, the D2 receptor exists as both D2 short (D2S) or D2 long (D2L), an extended variant with an additional 29 amino acids.1-4,6-9 The D4 receptor gene, DRD4, is highly polymorphic in the humans, particularly in the region that codifies the i3 loop, with variant number of tandem repeats of 48 nucleotides, which code from 2 to 11 hexadecapeptide repeats (D4.2-D4.11).1-4,6-9 The most predominant allelic frequencies are D4.2 (~9% of population), D4.4 (~65% of population), and D4.7 (~19% of population); importantly, these variations have been shown to have no impact on G protein (Gαi/o) coupling.1-4,6-10 Overall, a diverse array of approved medications target DRs and constitute the standard of care in schizophrenia, Parkinson’s disease (PD) and numerous other diseases; however, there are very few highly selective ligands for individual DR subtypes or that possess clean ancillary pharmacology against related biogenic amine receptors (adrenergic, muscarinic, serotonin, etc…).1-4,6-9 Indeed, DR-targeting drugs are highly effective and represent an early example of the therapeutic benefit of polypharmacology in complicated diseases. However, from a basic science perspective, the lack of highly selective small molecule tools has made it challenging to truly dissect the pharmacology and therapeutic potential of activation/inhibition of individual DR subtypes and recapitulate the exciting data derived from DR (-/-) mice.11,12 In this Perspective, we will review the historical data on D4 pharmacology and ligands, and then highlight recent advancements with next generation of D4 ligands and the evolving therapeutic potential of truly selective inhibition of D4.



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Insert [Figure 1]

1.2

Dopamine D4 receptor. The dopamine D4 receptor (D4) is encoded by the DRD4 gene

and numerous studies have associated it with psychiatric disorders (schizophrenia and bipolar disorder),

addictive

behaviors,

PD,

eating

disorders

(such

as

anorexia

nervosa),

impulsivity/novelty seeking and, for the D4.7 variant, attention deficit hyperactivity disorder (ADHD).1-4,11-19 However, these findings are not without controversy, and in many cases, results have not replicated or withstood further scrutiny. The strongest associations for D4 still remain for novelty seeking, substance abuse disorders (SUD) and ADHD (22% increase if carry the D4.7 variant).1-4,11-19

In terms of expression, D4 has the lowest level of expression of the five DR

subtypes; however, the predominant localization of D4 receptors in the brain is the frontal cortex (D4 receptor mRNA), as well as other areas (amygdala, hippocampus, globus palidus, substantia nigra pars compacta and thalmus) and the periphery (retina, kidney, adrenal glands, sympathetic ganglia, blood vessels, heart and the gastrointestinal tract).1-4,11-18 A recent report has shown that pyramidal cortical glutamatergic neurons are a main cellular localization of D4 receptors with important functional significance, and these neurons project to the striatum.19 In addition, this report indicates that activation of the D4 receptors inhibit corticostriatal glutamatergic transmission.19 Due to this localization, the therapeutic role of D4 in SUD and L-DOPA-induced dyskinesias are more compelling.19 Interestingly, studies have shown that D4 agonists improve retinal and visual function.20 The ability of GPCRs to form functional heterodimers is a hot topic in drug discovery, with heterodimers displaying unique and divergent pharmacology as compared to the classical


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homodimer congeners.2,21-23 The D4 receptor (D4.2, D4.4 and, to a lesser extent D4.7) has been shown to associate with both D2S and D2L to form heterodimers, which can potentiate D4 activation of MAPK.2,22,23 In addition, D4 has been shown to form a competent heterodimer with the β1 adrenergic receptor as well.23-26 However, selective ligands that discriminate between homo- and heterodimers are required in order to understand the therapeutic value or adverse effect liability of these novel molecular constructs, and existing D4 and D2 ligands have not been systematically evaluated against the D2/D4 heterodimers. Without question, this will be an exciting area of research in the coming years. The human D4 receptor was cloned and identified in a 1991 Letters to Nature account by Van Tol and co-workers as a new DR with high affinity for the antipsychotic clozapine (2).27 The newly identified D4 had high homology with D2/3 (>40%) and similar pharmacology, thus was grouped into the D2-like family of DRs. antipsychotics

in

terms

of

efficacy

in

As clozapine was unique amongst atypical schizophrenia

(especially treatment-resistant

schizophrenia) with low incidence of tardive dyskinesia, the finding in this report that the affinity of clozapine for D4 was an order of magnitude higher for D4 (Kd = 9 nM) than D2 and D3 and matches the plasma water concentration of 2 under therapeutic conditions.28,29 This report, and subsequent reports suggesting genetic associations of D4 in schizophrenic patients, 16,27 launched discovery efforts to develop D4 antagonists for the treatment of schizophrenia, as a next generation “clozapine” without the agranulocytosis risk. The enthusiasm and hope for this target cannot be emphasized enough – this was an exciting time in antipsychotic drug discovery.



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1.3

The discovery of 3.

In 1997, just 6 years after the discovery of the D4 receptor,

researchers from Merck published a series of manuscripts28,30,31 describing the discovery of a selective and CNS penetrant D4 antagonist, (3, (3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)1H-pyrrolo[2,3-b]pyridine)) along with ground breaking preclinical and clinical efficacy studies. Compound 3 possessed sub-nanomolar binding at D4 (Ki = 0.43 nM), 5- to 20-fold higher than the typical antipsychotic haloperidol (4, Ki = 2.3 nM) or 2 (Ki = 10 nM), respectively, and was >2,000-fold selective versus D1-3,5 (D1 Ki >10 µM, D2 Ki = 960 nM, D3 Ki = 2,310 nM, D5 Ki >10 µM). In addition, 3 counteracted dopamine-mediated inhibition of AC activation and [35S]GTPγS binding.30 This was truly unprecedented DR subtype selectivity with an orthosteric ligand at that time; however, the aryl piperazine moiety, a known GPCR privileged structure (e.g., promiscuous chemotype), results in off-target affinity at a number of biogenic amine GPCRs (e.g., sigma (Ki = 130 nM), adrenoreceptor α2A (Ki = 170 nM), adrenoreceptor α2B (Ki = 160 nM), adrenoreceptor α2C (Ki = 230 nM), adrenoreceptor α1C (Ki = 2,200 nM), adrenoreceptor α1B (Ki = 2,900 nM), serotonin 5HT2 (Ki = 200 nM), serotonin 5HT1A (Ki = 7,800 nM)).

The study indicated no activity at adenosine, muscarinic, neurotensin and

neurokinin receptors, but a broader ancillary pharmacology profile (binding and functional) has never been reported for 3.30 Thus, 3 is a D4 preferring ligand, with significant, potent off-target affinity, and results with 3 must be considered in this light.

Insert [Figure 2]


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Compound 3 was a good in vivo tool for studies in both rats (brain:plasma partition coefficient, Kp >10, 66% F and t1/2 = 2.1 h) and rhesus monkey (20% F and t1/2 = 2.8 h).30,31 Due to the excitement of 3 as a novel antipsychotic agent, it was tested in a number of preclinical behavioral paradigms. Unlike 2 and 4, 3 had no effect on prolactin levels and no effect on dopamine metabolism in several brain regions. While it dose-dependently (3-30 mg/kg, p.o.) reversed mescaline-induced head twitch, it did not exhibit a neuroleptic/antipsychotic-like profile in rodents (no effect in amphetamine-induced hyperlocomotion (AHL), conditioned avoidance responding (CAR), prepulse inhibition (PPI), apomorphine-induced stereotypy assays) and at high doses (100 mg/kg) induced extrapyramidal side effects (EPS). In naïve rhesus monkeys, 3 reduced locomotor activity, increased PD-like behaviors and induced sedation. Thus, inhibition of D4 did not display the same efficacy as clozapine in these assays, leading the authors to suggest that D4 was not behind the efficacy of 2.31 Also, in 1997, Merck reported on the effect of 3 in acutely psychotic inpatients with schizophrenia.28 In this trial, 38 acutely psychotic and neuroleptic responsive patients were randomized (2:1) with either 3 (n = 26, 15 mg/day) or placebo (n = 12) after a 3-5 day placebo run-in period.

About a third of the patients treated with 3 discontinued the study due to

insufficient therapeutic response. After 4 weeks, the brief psychotic rating scale favored placebo, and a large percentage of 3-treated patients reported worsening of symptoms.

Thus, the

clinicians concluded that 3 was ineffective as an antipsychotic agent for the treatment of neuroleptic responsive patients with acute schizophrenia.28

While issues could be raised

regarding patient selection (should they have explored drug naïve or first episode patients and/or a higher dose of 3), these combined negative preclinical and clinical disclosures with the D4-



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preferring antagonist 3, had a major impact on interest in D4 as a target, and little attention was focused on D4 for over a decade after these publications.

2. HISTORICAL D4 RECEPTOR LIGANDS

2.1

Aryl-linked Piperazine Analogs. Historical dopamine 4 receptor (D4R) antagonists

(late-1990’s onward) shared a common structural feature:

a core piperazine or piperidine

scaffold with aromatic rings flanking either side separated by a linker.32 Due to a similar moiety being found in other dopamine receptor ligands (basic nitrogen core scaffold), selectivity has been a challenge; although this has been overcome in some ligands via modulation of the linker length – which is generally shorter in D4R selective compounds (1 – 3 carbons).32 All of these initial scaffolds maintained the aryl-piperazine moiety but were distinct in the linker portion of the molecule (right-hand side of molecule, Figure 3, Table 1). Compounds 5 and 6 maintained the 4-chlorophenyl group and modified the benzylic heterocyclic functionality from the pyrrolo[2,3-b]pyridine of 3 to pyrazolo[1,5-a]pyridine structure.33

These compounds were

rationally designed using a pharmacophore model derived from a CoMFA study.34,35 Although these compounds maintained significant potency against the D4.4 receptor, they were ~10-fold less potent than 3. Very limited selectivity data has been published for these compounds. Both Abbott Laboratories36 and Pfizer37 disclosed 2-benzimidazoles as replacements for the pyrrolo[2,3-b]pyridine group (7 and 8). Compound 7 (A-381393) displayed a Ki = 1.5 nM against D4 (no subtype reported)36 whereas 8 (PD89211) had a Ki = 3.6 nM against D4.2.37 Both showed reasonable selectivity against other dopamine receptors (~1,000X) and against selected receptors; although 7 showed activity against 5-HT2A (Ki = 370 nM). Compound 9 replaced the


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pyrrolo[2,3-b]pyridine with a benzo[b][1,4]oxazin-3(4H)-one moiety.38 This compound was far less selective against other reported dopamine receptors (~100-fold selective vs. D2 and D3); however, 9 was active in vivo in pre-clinical models of schizophrenia.38

Two disclosed

compounds (10 and 11), replaced the aryl group with a heteroaryl group (2-pyrimidine).39,40 Neurogen Corporation disclosed compound 10 (NGD 94-1) and showed that it was equipotent against three D4 isoforms (D4.2, D4.4, and D4.7) and selectivity against the other dopamine receptors; however, it did have activity against 5-HT1A (Ki = 180 nM).39 Compound 10 was unique in that it contained a substituted imidazole core and not the bicyclic cores previously reported.39 Pfizer disclosed 11 (CP-293,019) as another unique dopamine scaffold that contains a central octahydro-2H-pyrido[1,2-a]pyrazine scaffold.40

In addition, 11 contains a

phenoxymethyl group, a group that is incorporated in the morpholine scaffolds (vide infra). Compound 11 is a potent antagonist of D4.4 with a Ki = 3.4 nM; however, it showed activity against both 5-HT1A and 5-HT2A (Ki = 180 and 500 nM, respectively).40 In addition, 11, in vivo inhibited the hyperactivity produced by apomorphine – a preclinical behavioral model of schizophrenia.40

Another compound with a novel benzoindane moiety, 12 (S 18126), was

discovered at Servier and reported in 1998.41 Much like the other piperazine-based antagonists, 12 was potent against D4.4 (Ki = 2.4 nM) but possessed varying selectivity against other receptors (α2Α, Ki = 249 nM), but significant activity against σ1 (Ki = 1.6 nM). Additional D4 antagonists were reported which extended the linker to a two-carbon spacer (13 – 15). Compound 13 (PNU96415E) contains an isochromane structure and is a potent antagonist of D4 (Ki = 3.0 nM) and 5HT2A (Ki = 5.8 nM) and was active in vivo.42

Compound 14 (PD-168568) contains an

isoindolinone and is selective for the D4 receptor versus D2 and D3, although no other selectivity data is given.43 Compound 15 (U-101387, Sonepiprazole), another isochromane containing



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structure, was potent and selective for the D4 receptor.44 Compound 15, like 3, was evaluated in a placebo-controlled clinical trial for schizophrenia, and like 3, 15 showed no benefits in the clinical trial.45 Lastly, a three-carbon spacer was introduced containing a chiral cyclopropane, 16, by Neurogen Corporation.46 However, this compound was not selective for D4 and was characterized as a D2/D4 mixed antagonist.46 Insert [Figure 3] Insert [Table 1] 2.2

Acetamide-linked piperazine analogs.

Another set of piperazine-based antagonists

from Neurogen Corporation contain a substituted benzylic group along with an acetamide functionality (17 – 19, Figure 4, Table 2). The secondary acetamide 17 was designed and had moderate potency at D4 (Ki = 59 nM), but was selective for D2, and molecular modeling studies indicated that the most favorable orientation was the cisoid as shown in Figure 4.47 Based on this orientation, the group designed a set of cyclic constrained analogs with 18 being a representative example. Compound 18 was ~15-fold more potent at D4 (Ki = 4 nM) than the acyclic 17; however, it was also more potent at D2 (Ki = 133 nM).47 From these analogs, the group then disclosed a novel and chiral indoline containing analog, 19.48 However, introduction of the chiral indoline moiety did not improve the selectivity for the D2 receptor and thus this class of compounds is characterized as mixed D2/D4 antagonists. Much like predecessor compounds, 19, was active in preclinical animal models of schizophrenia; however, due to the significant D2 activity, it was summarized that the antipsychotic activity may be due to this versus the D4 activity.48


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Insert [Figure 4] Insert [Table 2]

2.3

Piperidine-based analogs. In addition to the piperazine core scaffold, a number of

piperidine-based D4 antagonists have been reported (Figure 5, Table 3). Merck Sharp and Dohme identified a series of piperidine-based antagonists from high-throughput screening campaign of their internal sample collection.49 The initial hits contained a piperidine pyrazole core scaffold which, after medicinal chemistry efforts, identified a piperidine isoxazole core scaffold as a D4 antagonist (20, L-741,742), but has significant activity against D3 (Ki = 480 nM).49,50 Another piperidine-based scaffold was reported by a group from the University of Liége and contained a naphthamide, 21.51 A number of positional isomers of the naphthyl group were evaluated with the 2-naphthamide being the best. Compound 21 had similar potency at D4.2 and 5-HT2A (Ki = 11 and 44 nM, respectively); however, it was selective against D2L (Ki >1000 nM).51 A similar aminopiperidine scaffold containing a pyridine moiety, presumably with the pyridine serving as a masked amide, was reported by Kula and co-workers at Harvard Medical School. Compound 22 (RBI-257) was a highly potent antagonist of D4 at subnanomolar values (Ki = 0.33 nM) and had varying selectivity against the other dopamine receptors, with significant activity at D2L and D3 (Ki = 568 and 145 nM, respectively).52 Compound 22 was also highly active at σ1,2 receptors (Ki = 82 nM), again, highlighting the non-selective nature of the piperidine scaffold, much like the piperazine compounds.32,52 Due to the promiscuous nature of the piperazine and piperidine scaffolds, the identification of alternative moieties was initiated and some of those results are listed below.



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Insert [Figure 5] Insert [Table 3] 2.4

Morpholine-based analogs.

Although the majority of the historical D4 antagonist

ligands were based on either a piperazine or piperidine core scaffold, work was being conducted to find alternative scaffolds. One such effort was from the Merck Sharp and Dohme laboratories looking for isosteric alternatives to the previous scaffolds. As such, they identified the racemic morpholine scaffold as a selective D4 antagonist (Figure 6, Table 4).53 The group identified and characterized both the ethylene- and aryloxymethyl-linked compounds, 23 and 24.53 Both the carbon and aryloxymethyl-linked compounds, 23 and 24, were potent D4 antagonists (Ki = 6.2 and 5.6 nM, respectively) the compounds were active against both D2 and D3, with 24 having limited selectivity against D2 (Table 4). The group also reported initial in vivo PK results with representative compounds have bioavailability of >40%.53 After the initial Merck report, another group reported results for the morpholine and 1,4-oxazepane compounds, 25 and 26.54 This report, for the first time, established enantiopreference for the morpholine series with (S)-25 being 570-fold more potent than (R)-25. In addition, they showed the racemic 1,4-oxazepane scaffold, 26, was also a potent D4 antagonist (Ki = 4.9 nM).54 They also utilized a 3D-QSAR approach to better understand the SAR using the GRID/GOLPE methodology.55 Unfortunately, no selectivity data is reported for these compounds.

Insert [Figure 6]


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Insert [Table 4]

3. NEXT GENERATION D4 RECEPTOR LIGANDS

Due, in part, to the clinical failures of 3 and 15 (Sonepiprazole) interest in the D4 receptor waned significantly in the mid-late 2000s and into the early-2010s. In 2012, the Vanderbilt group published a synthetic methodology procedure for the synthesis of chiral morpholines and piperazines.56 Having this novel methodology at their disposal, the group synthesized a chiral morpholine compound that had been reported in the patent literature as a racemic mixture, (rac)27 (Figure 7, Table 5).57

It was shown here that the morpholine compounds possess

enantiopreference for the D4 ligand – confirming the previous report.54,56

From this, the

Vanderbilt group has published several manuscripts detailing their work on further advancement of the chiral morpholine series. In 2014, the group published an SAR evaluation around these chiral scaffolds culminating in the discovery of (R)-28 (ML398), which is a potent (D4.4 Ki = 36 nM) and selective D4 receptor antagonist.58 In addition, to the in vitro characterization, the group showed that (R)-28 was highly brain penetrant (B:P = 2.0) and reversed cocaine-induced hyperlocomotion at 10 mg/kg after systemic administration.58 However, the SAR revealed in this report was limited to the morpholine nitrogen attached moieties due to synthetic challenges around modification of the ethylene linked phenyl groups. Due to this, in 2016, the Vanderbilt group moved to the chiral aryloxymethyl morpholine analogs, (S)-29.59 The aryloxymethyl linker allowed for the ease of diversification on both sections of the molecule and the group identified (S)-29, a prototypical compound with high potency against D4.4 (Ki = 14.3 nM) and



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>150-fold selectivity versus the other dopamine receptors.59 These analogs also were shown to be highly brain penetrant with B:P > 2 for most analogs tested. In addition to the morpholine analogs, in 2016, the Vanderbilt group also revealed a novel, chiral 4,4-gem-difluoropiperidine scaffold with high potency and selectivity.60 The group identified (R)-30 as key compound which is highly potent and selective for D4.4 (Ki = 5.8 nM,

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