Development of Adenosine A2A Receptor Antagonists for the

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Review

Development of Adenosine A2A Receptor Antagonists for the Treatment of Parkinson’s Disease: a Recent Update and Challenge Jiyue Zheng, Xiaohu Zhang, and Xuechu Zhen ACS Chem. Neurosci., Just Accepted Manuscript • Publication Date (Web): 10 Sep 2018 Downloaded from http://pubs.acs.org on September 10, 2018

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ACS Chemical Neuroscience

Development of Adenosine A2A Receptor Antagonists for the Treatment of Parkinson’s Disease: a Recent Update and Challenge

Jiyue Zheng, Xiaohu Zhang* and Xuechu Zhen*

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, P. R. China

1

ACS Paragon Plus Environment

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Abstract: Parkinson’s disease (PD) is a neurodegenerative disease with significant unmet medical needs. The current dopamine-centered treatments aim to restore motor functions of patients without slowing the disease progression. Long-term usage of these drugs is associated with diminished efficacy, motor fluctuation, and dyskinesia. Furthermore, the non-motor features associated with PD such as sleep disorder, pain and psychiatric symptoms are poorly addressed by the dopaminergic treatments. Adenosine receptor A2A antagonists have emerged as potential treatment for PD in the past decade. Here we summarize the recent work (2015-2018) on adenosine receptor A2A antagonists and discuss the challenge and opportunity for the treatment of PD.

Keywords: adenosine receptor, antagonist, Parkinson’s disease, GPCR.

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1.

INTRODUCTION

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer’s disease (AD), and affects about 1.5% of the population over the age of 60.1 As life expectancy increases, the number of individuals afflicted by Parkinson’s disease is expected to double by 2030.2 The crucial pathological feature of PD is death of the dopaminergic neuron in the midbrain. The dopamine deficiency within the basal ganglia leads to the characteristic motor symptoms of PD such as bradykinesia, muscle rigidity and resting tremor. Non-motor features such as sleep disorder, pain and psychiatric symptoms are also present in patients with PD. Thus, PD is currently viewed as a progressive neurodegenerative disease involves multiple neurotransmission pathways with a broad range of symptoms.3

The current clinical treatments for PD almost exclusively focus on the dopaminergic pathway to restore the motor symptom of PD.1,2 Pro-drug levodopa (L-DOPA) as dopamine replacement therapy has been the gold standard for providing symptomatic relief for PD patients with motor disorders. Although dopamine replacement treatment is effective in relieving the motor symptoms, however, chronic drug treatment is associated with diminished efficacy, dyskinesia and motor fluctuation4-6. Dual dopamine-serotonin receptor (particularly 5-HT1A receptor) agonists have been suggested to effectively reduce the dyskinesia while producing potent antiparkinsonian effect.7-10 Other treatment options include selective dopamine receptor agonists4 and monoamine oxidase-B (MAO-B) inhibitors11,12. Unfortunately, these treatments cannot delay or stop the disease progression. Long-term usage of these drugs is associated with diminished efficacy and side effects such as dyskinesia.13,14 Furthermore, these dopaminergic centered treatment options are not effective on treating non-motor features such as sleep

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disorder, pain and psychiatric symptoms in PD patients.15 Despite the clear unmet medical needs and the intensive investment from the pharmaceutical industry in PD research and development, only a couple of adjunct new treatments were achieved in the past decade. Istradefylline, an adenosine receptor A2A antagonist, received marketing approval in Japan in 2013 (discussed later).16 Safinamide, a compound with multiple modes of action which involves dopaminergic (mainly through reversible and selective inhibition of monoamine oxidase-B) and non-dopaminergic (mainly through modulation of voltage-gated sodium and N-type calcium channels) mechanisms17, received marketing approval in Europe in 201518 and in the United States in 201719, respectively. Safinamide is approved as an adjunctive therapy to levodopa for the management of motor fluctuation in mid to late-stage PD patients. Consequently, there is an urgent need for the development of novel therapeutic agents that address the limitations of the current dopamine-centered PD treatment, and ideally, for long term, disease-modifying therapies for PD management.3

The significant limitations of the dopaminergic replacement treatments for PD prompted scientific community to search for nondopamine- based treatments for PD. In the past decade, adenosine receptor A2A antagonists have emerged as potential nondopamine based treatments for PD. Adenosine is an important neuromodulator that exerts its functions through the interaction with A1, A2A, A2B and A3 subtypes in response to organ stress or tissue damage. A2A receptor belongs to the G-protein-coupled-receptors (GPCRs) superfamily, which couples to Gs protein and stimulates adenylate cyclase. In addition, A2A receptor physically interacts with D2 dopamine receptor and functionally acts as a negative regulator of D2 receptor.20,,21 In the central nervous system, adenosine is involved in memory, mood and motor functions. Adenosine receptor A2A is highly expressed and co-localized with dopamine D2 and D3 receptors on striatopallidal output neurons in the striatum.

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Activation of A2A receptor inhibits indirect basal ganglia pathway from striatum to thalamus via globus pallidus pars externa, subthalamic nucleus. Preclinical animal models as well as clinical studies have demonstrated that adenosine receptor A2A antagonists can improve motor dysfunctions of PD while reducing side effects such as dyskinesia. Furthermore, it is suggested that adenosine receptor A2A antagonists may have neuron protective functions and therefore can delay the onset and progression of PD.22 There have been a number of excellent reviews on A2A receptor antagonists dealing with medicinal chemistry23-25, structural based drug discovery26, and clinical outcomes27. This Review will highlight the most recent (2015-2018) medicinal chemistry efforts done on this target and analyze the opportunity and challenge utilizing A2A receptor antagonists for the treatment of PD.

2.

BRIEF UPDATE ON CLINICAL RESULTS OF A2A ANTAGONISTS FOR PD

The chemical structures and brief information of the adenosine receptor A2A antagonists that progressed into clinical testing are summarized in Figure 1 and Table 1, respectively. In general, A2A antagonists were well tolerated with good safety profile at the intended clinically efficacious doses. Although the selectivity profiles, in particular, A2A vs. A1, varied dramatically among the clinical compounds (e.g. ST1535, 12 folds; preladenant, over 1000 folds, Table 1), no significant systolic and diastolic blood pressure changes were observed in the clinical testing. The most common adverse effects (AEs) were dizziness, nausea and dyskinesia.27 A2A antagonists exhibited limited beneficial effects in PD patients as monotherapy. As adjunctive therapy, istradefylline (1), a xanthine based compound developed by the Japanese company Kyowa Hakko Kirin, demonstrated effectiveness in reducing the off-time (1-2 hours) in PD patients.27 Istradefylline received marketing approval in Japan

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on March 25, 2013 under the name of NOURIAST (20 mg orally administrated once daily).16 Istradefylline represents the first adenosine A2A antagonist for the treatment of PD patients. Preladenant (2), a potent and selective nonxanthine A2A antagonist (A2A 1.1 nM, A1/A2A > 1000, Table 1) developed by Merck, exhibited similar effectiveness in reducing the off-time (1-2 hours) in PD patients.28 However, the clinical benefit of these compounds was marginal and varied from different trials, leading to the disapproval of istradefylline in the US market29 and the discontinuation of preladenant30. Numerous factors may have contributed to the mixed clinical results, including suboptimal doses for levodopa, inappropriate control, and dietary consumption of caffeine in PD patients.

Figure 1. A2A receptor antagonists progressed into clinical testing

Table 1. Brief information of clinical A2A receptor antagonists

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Compound

A2A Ki (nM)

A2B Ki (nM)

A1 Ki (nM)

A3 Ki (nM)

Clinical trial ID

1, istradefylline31

12

1800

841

> 3000

2, preladenant32

1.1

> 1700

1474

> 1000

NCT00199394 NCT00199407 NCT00203957 NCT00955526 NCT00957203 NCT01968031 NCT02610231 NCT00537017 NCT01155466 NCT01155479 NCT01227265

3, ST153533

6.6

352

79.2

4, ST420634

12

ND

5, tozadenant35

5.0

6, vipadenant36 7, AZD463537

3.

Phase of clinical development Approved in Japan Disapproved in USA

Indications

Phase III (Discontinued)

Parkinson’ s disease

> 10000

Phase I

192

ND

Phase I

700

1350

1570

Phase III (Discontinued)

Parkinson’ s disease Parkinson’ s disease Parkinson’ s disease

1.3

63

68

1005

1.7

64

160

> 10000

Phase II (Discontinued) Phase II

Parkinson’ s disease cancer

NCT00605553 NCT01283594 NCT02453386 NCT03051607 NCT00438607 NCT00442780 NCT02740985 NCT03381274

Parkinson’ s disease

UPDATE ON DEVELOPMENT OF A2A RECEPTOR ANTAGONISTS

Adenosine A2A receptor antagonists have been traditionally categorized as xanthine and nonxanthine derivatives. Alternatively, based on their core structures, adenosine A2A receptor antagonists have been divided into monocyclic, bicyclic and tricyclic derivatives. Since most of the recently published compounds fell into this scope, we will summarize the most relevant compounds according to the core structures.

3.1 MONOCYCLIC A2A ANTAGONISTS (FIGURE 2)

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Figure 2. Examples of monocyclic A2A receptor antagonists

Heptares in collaboration with AstraZeneca is developing an A2A antagonist HTL001071/AZD4635 (7) for Parkinson’s disease and immuno-oncology indications (NCT02740985).38 The structure of the clinical compound was recently disclosed.37 In addition, Heptares had published a number of papers detailing their work on A2A antagonist program, exemplifies by compound 8.39 Compound 8 was a potent A2A antagonist (Ki = 3.5 nM) with moderate selectivity for A1 (about 9-fold). It had low activity towards other adenosine receptors, as well as CYP450 enzymes and hERG channel. When dosed orally at 2 mg/kg in rat, compound 8 was quickly absorbed into the blood stream with a Tmax at 0.4 h. The exposure was good with AUC = 846 ng·h/mL and a Cmax at 244 ng/mL. With moderate clearance (42 mL/min/kg) and volume of distribution (4.6 L/kg), compound 8 displayed an excellent bioavailability of F = 100%. In addition, compound 8 could cross the blood brain barrier and exhibited a plasma/brain ratio of 3.2 after 0.5 h of dosing. Compound 8 significantly reversed haloperidol-induced catalepsy in rats with ED50 values of 0.2 mg/kg at both 1 and 2 h post dose time points.

PaloBiofarma in collaboration with Novartis is developing an A2A antagonist PBF-509 (structure not disclosed) for Parkinson’s disease and non-small cell lung cancer (NCT02403193).40 A recent patent application

from

PaloBiofarma

particularly

claimed

8


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5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine (compound 9) for its use in the treatment of cancer.41 Compound 9 was formerly disclosed as a potent A2A antagonist with a binding of Ki = 12 nM and function of Ki = 25 nM in the cAMP assay.42 No further preclinical data is available for PBF-509.

We have recently developed a series of potent A2A antagonist by replacing the potentially unstable acetamide (compound 10) based on the 4-aminepyrimidine template exemplified by compound 11.43,44 Numerous compounds with improved chemical stability, excellent binding affinity and functional potency were achieved. Compound 11 displayed a binding affinity of Ki = 0.22 nM, potently inhibited cAMP production in cell based assay (IC50 = 2.1 nM), crossed the blood brain barrier (B/P ratio at 1.6) and demonstrated significant reversal of haloperidol-induced catalepsy in rat when dosed i.p. at 5, 10, and 30 mg/kg. Nevertheless, the high clearance in human and mouse (57 and 680 mL/min/kg, respectively) liver microsomes prevented compound 11 from being further profiled in additional safety and efficacy evaluation. Subsequent modification with the help of molecular docking studies identified a series of potent A2A antagonist based on a 4-amino-5-carbonitrile pyrimidine template.45 Compound 12 potently bound to A2A receptor (Ki = 1.0 nM), inhibited cAMP production in cell based assay with an IC50 = 1.1 nM. More importantly, compound 12 exhibited minimal CYP450 enzymes inhibition at 10 µM and improved clearance in human and mouse liver microsomes compared with 11. When dosed orally at 10 mg/kg, compound 12 significantly reversed the haloperidol-induced catalepsy.

Researchers from Lundbeck reported their work to improve aqueous solubility and other druglike properties of a series of compounds based on a 2-amino thiazole template.46 Compound 14 bound with human A2A receptor with an affinity of Ki = 110 nM. Although the binding affinity suffered moderately compared with the starting point (13, Ki = 5.9 nM), compound 14 displayed a number of improvements. Compound 14 showed no significant inhibition of CYP450 enzymes, displayed low in vitro clearance

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in human liver microsomes (hClint = 0.62 L/kg/h), and much improved aqueous solubility (116 µg/mL at pH 7.4 for 14 vs 1 µg/mL for 13). Scientists from North-West University, South Africa disclosed a series of A2A/A1 antagonists based on a 2-amino pyrimidine template. Compound 15 was a potent dual antagonist with binding affinity of 6.3 nM and 9.5 nM at A2A and A1 receptor, respectively. In addition, compound 15 significantly attenuated haloperidol-induced catalepsy at dose as low as 0.1 mg/kg after i.p. dosing in rat.47 A close analogue of 15, compound 16 maintained high affinity at both A2A (Ki = 2.7 nM) and A1 receptors (Ki = 3.5 nM). Similarly, compound 16 reversed haloperidol-induced catalepsy at dose as low as 0.1 mg/kg after i.p. dosing in rat.48

3.2 BICYCLIC A2A ANTAGONISTS (FIGURE 3)

Many of the A2A antagonists progressed into the clinical testing features a bicyclic core structure. Xanthine based istradefylline (1) received marketing approval in Japan on March 25, 2013.16 However, istradefylline was not approved in the US market.29 Other non-xanthine bicyclic compounds (e.g. ST1535, tozadenant) are in various stages of clinical testing. Recent acquisitions of Biotie (tozadenant) by Acorda Therapeutics49 and Redox (vipadenant) by Juno Therapeutics50 highlighted the continued interests in A2A antagonists for the potential treatments of PD and immuno-oncology indications. The latest research activities mainly focused on the modifications and extensions of the known structural scaffolds (Figure 3).

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Figure 3. Examples of bicyclic A2A receptor antagonists/partial agonists/inverse agonists

A series of adenosine derivatives was reported as potent A2A antagonist with moderate selectivity for other adenosine receptors exemplified by compounds 17 (A2A Ki = 6.6 nM, A1 Ki = 138 nM)51 and 18 (A2A Ki = 6.8 nM, A1 Ki = 143 nM)52. A number of compounds were designed and synthesized to mitigate the metabolic soft spot of ST1535 (3). Compound 19 was identified as a potent A2A antagonist (A2A Ki = 2.2 nM) with much improved metabolic stability.53 In HLM, ST1535 (3) was rapidly degraded with a half-life of 13.7 min while 19 remained almost unchanged after 2 h. In an effort to comprehensively profile heterocyclic derivatives as adenosine receptor antagonists, compounds 20 (A2A Ki = 1.1 nM, A1 Ki = 95 nM)54, 21 (A2A Ki = 123 nM, A1 Ki = 25 nM)55, 22 (A2A Ki = 3.6 nM, A1 Ki = 18 nM)56, 23 (A2A Ki = 265 nM, A1 Ki = 210 nM)57, and 24 (A2A Ki = 7.2 nM, A1 Ki > 30000 nM)58 had been identified as potent A2A antagonists. Compound 24 was an exceptionally selective A2A antagonist with no activity for other adenosine receptors (A1, A2B, and A3 > 30000 nM). In addition, the

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substitutions on the phenyl A ring (Figure 3, 24) had huge impact on receptor binding affinity and selectivity. For example, while 24 was a selective A2A antagonist, its des-methyl phenol analogue was active towards other receptors (A1 Ki = 45 nM, A2A Ki = 45 nM, A2B IC50 > 30000 nM, and A3 Ki = 53 nM). Surprisingly, displacement of the methoxy with a methyl group completely abolished activity towards all receptor

subtypes (A1,

A2A, A2B,

and

A3

>

30000

nM). This

peculiar

structure-activity-relationship was difficult to be explained by the docking studies, as no significant polar interactions/size collisions were observed. Compound 23 was able to protect human neuroblastoma SH-SY5Y cells from MPP+-induced neurotoxicity in culture medium. Fused bicyclic oxazoles and thiazoles had been reported to be A2A antagonists. Compound 25 bound to A2A receptor and functioned as an antagonist (A2A Ki = 40 nM,

35

GTPγS IC50 = 81 nM), displayed

decent in vitro DMPK properties (solubility 31 µM, 10% unbound fraction with plasma proteins, good permeability, not a Pgp substrate, and > 60 mins t1/2 in human liver microsomes).59 Compound 26, a very close analogue of tozadenant (5), was reported to be potent A2A antagonist with good selectivity (A2A Ki = 2.1 nM, A1 Ki = 1200 nM, A2B Ki = 500 nM, and A3 >30000 nM).60 It displayed comprehensively good physicochemical properties and in vitro safety profiles (aqueous solubility 1600 µM at pH 7.4, CYP450 > 50 µM, high permeability and no hERG inhibition over 30 µM). In addition, it was metabolically stable in RLM and HLM as well as in rat hepatocytes, which translated into good in vivo pharmacokinetic profiles in rat (i.v. 3 mg/kg, p.o. 10 mg/kg, Cmax 2 µM, Tmax 0.63 h, AUC0-t 5.5 µM·h/p.o., Vss 6.1 L/kg, t1/2 2.4 h, F% = 61%). It bound moderately with serum protein (76%) and had low brain penetration (0.25 brain/plasma ratio in rat). When tested in the 6-hydroxydopamine lesioned rats, compound 26 showed significant effect on potentiation of L-DOPA induced contralateral rotations only at the higher dose tested (100 mg/kg, p.o.), while the positive control tozadenant (5) showed

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comparable efficacy at 30 mg/kg oral dosing. This could be the reflection of the low brain exposure; however, nonspecific binding in the brain associated with the basic amine presented in 26 might also contribute to the observed moderate efficacy in the 6-hydroxydopamine lesioned rats. A series of 7-prolinol-substituted thiazolo[5,4-d]pyrimidine derivatives was reported to be potent partial agonist of A2A receptor.61 Compound 27 (A2A Ki = 200 nM, A1 Ki = 555 nM, A3 Ki = 973 nM) elicited 60% agonist activity at 10 µM while its pyrrolidine analogue (A2A Ki = 351 nM) displayed no such activity. Although A2A agonistic activity is not generally considered to be beneficial for PD, 27 provided a useful

tool

for

pharmacological

characterization

of

A2A

receptor.

A

variety

of

2-(2-furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine derivatives were reported to be potent A2A receptor antagonist/inverse agonist.62 Compound 28 exhibited exceptional A2A receptor binding affinity by displacing two distinct radio ligands in a biphasic manner (A2A Kh = 3.55 fM, Kl = 6.45 nM for displacing 3H ZM 241385, for example). Compound 28 was able to inhibit basal cAMP accumulation at picomolar concentrations in cells (IC50 = 1.9 pM) with an efficacy of 63%. Compound 28 showed antinociceptive activity equal to or greater than that of morphine in two acute animal experimental models of pain. It would be interesting to test 28 in other disease indications including PD. A series of 2-amine quinazoline derivatives was reported to be potent A2A receptor antagonist.63 Compound 29 (A2A Ki = 0.5 nM, A1 Ki = 12 nM) displayed good exposure (AUC = 2.4 µM·h, 10 mg/kg, p.o.) after oral doing and significantly reversed haloperidol-induced catalepsy in rat. A variety of xanthine derivatives were synthesized.64 Compound 30 (A2A Ki = 237 nM, A1 Ki = 1220 nM) showed moderate A2A activity and selectivity over other adenosine receptors. We recently performed an extensive docking-based virtual screening (VS) in an effort to identify A2A antagonist with novel structures.65 Compound 31 (A2A Ki = 54 nM) was found to be a potent A2A antagonist with moderate

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selectivity over A1. Compound 31 significantly attenuated haloperidol-induced catalepsy in rat at dose as low as 3 mg/kg/i.p..

3.3 TRICYCLIC A2A ANTAGONISTS (FIGURE 4) Fused tricyclic structures had been extensively utilized in pursuit of A2A antagonist programs. Preladenant (2) was a potent A2A antagonist (A2A Ki = 1.1 nM) with excellent selectivity over other adenosine receptor subtypes.32,66 Preladenant went through extensive preclinical and clinical testing but was discontinued due to lack of efficacy in phase III clinical trials for PD.30 A number of tricyclic scaffolds were synthesized as an effort to comprehensively profile heterocyclic derivatives as adenosine receptor antagonists.67 Compounds 32 (A2A Ki = 104 nM, A1 Ki > 1000 nM, A2B Ki > 1000 nM, and A3 Ki = 1.16 nM), 33 (A2A Ki = 346 nM, A1 Ki = 184 nM, A2B Ki = 283 nM, and A3 Ki = 468 nM), and 34 (A2A Ki = 13.6 nM, A1 Ki = 67.7 nM, A2B Ki = 75 nM, and A3 Ki > 1000 nM) had been identified as A2A antagonists with various selectivity profiles towards other adenosine receptors. These scaffolds could serve as valuable starting points for specific pharmacological needs. A series of triazolo quinazoline derivatives was synthesized as potent A2A antagonists with reduced hERG channel activity.68 Molecular docking with an A2A receptor crystal structure and matched molecular pair of available hERG data helped to elucidate the modification point of this series of compounds. As a result, compound 35 (A2A Ki = 24.6 nM, A1 Ki = 16,000 nM, hERG > 60,000 nM) was identified as a potent A2A antagonist with good selectivity and no hERG liability. Xanthine derivatives continued to be a point of interest in designing A2A antagonists.69,70 Compound 36 (A2A Ki = 595 nM, A1 Ki = 393 nM) was identified as an A2A/A1 dual antagonist. In addition, it also displayed inhibition of human MAO-B (IC50 = 210 nM), which might offer synergetic beneficial effect for the treatment of PD. Compound 37

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(A2A Ki = 1.5 nM, A1 Ki = 1700 nM, A2B Ki = 5000 nM, and A3 Ki > 10,000 nM), a close analogue of preladenant (2), was reported to be a potent and selective A2A antagonist.71 Compound 37 displayed good metabolic stability in mouse, rat, dog and human liver microsomes and no significant inhibition of hERG channel and the major CYP450 enzymes. In addition, 37 exhibited decent overall pharmacokinetic profiles in rat (i.v. 3 mg/kg, p.o. 10 mg/kg, Cmax 0.6 µM, Tmax 0.8 h, AUC0-t 2.2 µM·h/p.o., Vss 3.6 L/kg, t1/2 1.0 h, F% = 32%). It bound moderately with plasma protein (85% for human and 82% for rat) and had moderate brain penetration (0.38 brain/plasma ratio in rat). Furthermore, 37 displayed good efficacy in two animal models of PD: when dosed orally in rat, 37 significantly attenuated haloperidol-induced catalepsy with an ED50 of 4.5 mg/kg; compound 37 also dose-dependently potentiated L-DOPA-induced contralateral rotations in the 6-hydroxydopamine lesioned rats with an ED50 of 1.2 mg/kg. Finally, compound 37 improved motor functions without causing dyskinesia in rat model of PD.

Figure 4. Examples of tricyclic A2A receptor antagonists

3.4 SUMMARY OF SAR AND PROSPECTIVE

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Many compounds reported in the past five years were based on old templates. For example, compounds 2660 and 3771 went through comprehensive evaluation for their in vitro potency, selectivity and safety, as well as in vivo pharmacokinetic, pharmacodynamic and efficacy profile. Compounds 26 and 37 are structurally close analogues to tozadenant and preladenant, respectively. Although these compounds may obtain new intellectual property position, they provide limited improvement as potential PD treatment. Compound 2862 exhibited exceptional property as an extremely potent adenosine A2A inversed agonist. Interestingly, the chemical scaffold of 28 is not distinctively different from other A2A templates. It would be very interesting to test 28 in animal PD models. Structure optimization is often led by breakthrough pharmacological discovery exemplified by the intriguing property of compound 28. Further structural exploration and optimization may lead to more exciting compounds.

4.

CONCLUSION REMARK

Although dopamine replacement therapy remains the most effective drug in relieving the motor symptoms in PD patients, the development of dyskinesia and motor fluctuation associated with chronic dopaminergic agent administration becomes a major challenge. Non-dopamine based therapies have emerged as alternative approaches in PD drug development. Adenosine A2A receptors are expressed in basal ganglia nuclei which is known to regulate motor activity by acting at different levels: either modulating the balance between indirect or direct pathways of basal ganglia, or altering the dopamine receptor activity through physical and functional interaction with dopamine receptor. Istradefylline (KW-6002), developed by Kyowa Hakko Kirin, is the most advanced A2A receptor antagonist.72 On March 25, 2013, istradefylline received marketing approval in Japan.16 However, istradefylline was not approved in the US market.29 The clinical development of another promising A2A receptor antagonist,

16


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preladenant66, was discontinued due to lack of efficacy30. The mixed clinical results underscore the challenge for the development of novel therapeutics for PD. One may argue that the intrinsic properties may underline the mixed clinical responses with different chemical structures. It should be pointed out that several clinical trials have found that administration of A2A receptor antagonist did not produce a significant improvement on dyskinesia but with reduction in the OFF time in dyskinesia.28,73,74 Future work may focus on finding out if addition of A2A receptor antagonist to lower dose of dopamine agent can reduce or prolong the development of dyskinesia. In addition, given the complexity of A2A receptor interacting with other neurotransmitter receptors in the central nervous system, rational design of multifunctional A2A receptor modulator (e.g. A2A/A1, A2A/D2,3, A2A/5-HT1A, A2A/H3) may also be a promising approach for the treatment of PD.

ASSOCIATED CONTENT

Supporting Information

Receptor binding affinities of discussed compounds were tabulated. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION

Corresponding Author

*(X.H.Z.) Mailing address: Soochow University College of Pharmaceutical Sciences, 199 Ren Ai Road, Suzhou, Jiangsu, P.R.China 215123. 65880380.

Fax: (86)512 65880380.

E-mail: [email protected].

Telephone: (86)512

(X.C.Z.) Mailing address: Soochow University College of

Pharmaceutical Sciences, 199 Ren Ai Road, Suzhou, Jiangsu, P.R.China 215123. E-mail: [email protected]. Telephone: (86)512 65880369. Fax: (86)512 65880369.

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Author Contributions

J.Z. and X.H.Z. outlined and performed literature search. X.H.Z. and X.C.Z wrote the manuscript.

Funding

This work was supported by National Natural Science Foundation of China (Grant No. 81773561, 81473090, 81773702); BM2013003, and PAPD (A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions).

Notes The authors declare no competing financial interest. ABBREVIATIONS

AD, Alzheimer’s disease; AE, adverse effect; AUC, area under the curve; B/P, brain/plasma; CYP450, cytochrome P450; DMPK, drug metabolism and pharmacokinetics; L-DOPA, levodopa; GPCR, G protein-coupled receptor; hERG, human ether-a-go-go-related gene; HLM, human liver microsomes; i.p., intraperitoneal injection; Kh, the high affinity Ki value; Kl, the low affinity Ki value; MAO-B, monoamine oxidase-B; MPP+, 1-methyl-4-phenyl-pyridinium; PD, Parkinson’s disease; Pgp, P-glycoprotein; p.o., per oral; RLM, rat liver microsomes; VS, virtual screening.

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For Table of Contents Use Only

Development of Adenosine A2A Receptor Antagonists for the Treatment of Parkinson’s Disease: a Recent Update and Challenge

Jiyue Zheng, Xiaohu Zhang* and Xuechu Zhen*

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, P. R. China

Graphical Abstract

Parkinson’s disease (PD) is a neurodegenerative disease with significant unmet medical needs. The current dopamine-centered treatments aim to restore motor functions of patients without slowing the disease progression. Long-term usage of these drugs is associated with diminished efficacy, motor fluctuation, and dyskinesia. Furthermore, the non-motor features associated with PD such as sleep disorder, pain and psychiatric symptoms are poorly addressed by the dopaminergic treatments. Adenosine receptor A2A antagonists have emerged as potential treatment for PD in the past decade. Here we summarize the recent work (2015-2018) on adenosine receptor A2A antagonists and discuss the challenge and opportunity for the treatment of PD.

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Development of Adenosine A2A Receptor Antagonists for the

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