Discovery of clinical candidate 1-(4-(3-(4-(1 H-benzo[ d ]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), A potent, selective, and efficacious inhibitor of phosphodiesterase 10A (PDE10A)

Journal of Medicinal Chemistry

Volumn 57, Issue 15, 2014, Pages 6632-6641

  Hu, Essa ^a   Chen, Ning ^a   Bourbeau, Matthew P ^a   Harrington, Paul E ^a   Biswas, Kaustav ^a   Kunz, Roxanne K ^a   Andrews, Kristin L ^a   Chmait, Samer ^a   Zhao, Xiaoning ^a   Davis, Carl ^a   Ma, Ji ^a   Shi, Jianxia ^a   Lester Zeiner, Dianna ^a   Danao, Jean ^a   Able, Jessica ^a   Cueva, Madelyn ^a   Talreja, Santosh ^a   Kornecook, Thomas ^a   Chen, Hang ^a   Porter, Amy ^a   Hungate, Randall ^a   Treanor, James ^a   Allen, Jennifer R ^a   more..

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (4 (3 (4 (1 BENZO[D]IMIDAZOLE 2 CARBONYL)PHENOXY)PYRAZIN 2 YL)PIPERIDIN 1 YL)ETHANONE; BENZIMIDAZOLE DERIVATIVE; CARBON; MORPHOLINE; N ACETYLPIPERAZINE; NITROGEN; PHOSPHODIESTERASE; PHOSPHODIESTERASE 10A; PHOSPHODIESTERASE INHIBITOR; PIPERAZINE DERIVATIVE; PYRAZINE DERIVATIVE; PYRIDINE DERIVATIVE; TETRAHYDROPYRAN DERIVATIVE; UNCLASSIFIED DRUG; 1-(4-(3-(4-(1H-BENZO(D)IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE; NEUROLEPTIC AGENT; PDE10A PROTEIN, HUMAN;

ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; ATOM; BINDING AFFINITY; BRAIN REGION; CONFORMATION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DOSE RESPONSE; DRUG EFFICACY; DRUG POTENCY; HYDROGEN BOND; IN VIVO STUDY; LIQUID CHROMATOGRAPHY; LOCOMOTION; MALE; MASS SPECTROMETRY; NONHUMAN; RAT; SCHIZOPHRENIA; STRUCTURE ACTIVITY RELATION; ANIMAL; BIOAVAILABILITY; BRAIN; CHEMISTRY; DOG; DRUG EFFECTS; HUMAN; METABOLISM; MOTOR ACTIVITY; ORAL DRUG ADMINISTRATION; PRIMATE; PROTEIN CONFORMATION; SPRAGUE DAWLEY RAT; SYNTHESIS;

ADMINISTRATION, ORAL; ANIMALS; ANTIPSYCHOTIC AGENTS; BENZIMIDAZOLES; BIOLOGICAL AVAILABILITY; BRAIN; DOGS; HUMANS; MALE; MOTOR ACTIVITY; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; PRIMATES; PROTEIN CONFORMATION; PYRAZINES; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84906085755     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm500713j     Document Type: Article

References (38)

1. Chappie, T. A.; Helal, C. J.; Hou, X. Current landscape of Phosphodiesterase 10A (PDE10A) inhibition J. Med. Chem. 2012, 55, 7299-7331
2. Soderling, H.; Bayuga, J.; Beavo, A. Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 7071-7076
3. Seeger, T. F.; Bartlett, B.; Coskran, T. M.; Culp, J. S.; James, L. C.; Krull, D. L.; Lanfear, J.; Ryan, A. M.; Schmidt, C. J.; Strick, C. A.; Varghese, A. H.; Williams, R. D.; Wylie, P. G.; Menniti, F. S. Immunohistochemical localization of PDE10A in the rat brain Brain Res. 2003, 985, 113-126
4. Lakics, V.; Karran, E. H.; Boess, F. G. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues Neuropharmacology 2010, 59, 367-374
5. Nishi, A.; Kuroiwa, M.; Miller, D. B.; O'Callaghan, J. P.; Bateup, H. S.; Shuto, T.; Sotogaku, N.; Fukuda, T.; Heintz, N.; Greengard, P.; Snyder, G. L. Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum J. Neurosci. 2008, 28, 10460-10471
6. Siuciak, J. A.; McCarthy, S. A.; Chapin, D. S.; Fujiwara, R. A.; James, L. C.; Williams, R. D.; Stock, J. L.; McNeish, J. D.; Strick, C. A.; Menniti, F. S.; Schmidt, C. J. Genetic deletion of the striatum-entriched phosphodiesterase PDE10A: evidence for altered striatal function Neuropharmacology 2006, 51, 374
7. Siuciak, J.; McCarthy, S.; Chapin, D.; Martin, A.; Harms, J.; Schmidt, C. Behavioral characterization of mice deficient in the phosphodiesterase-10A (PDE10A) enzyme on a C57/Bl6N congenic background Neuropharmacology 2007, 54, 417-427
8. Grauer, S. M.; Pulito, V. L.; Navarra, R. L.; Kelly, M. P.; Kelley, C.; Graf, R.; Langen, B.; Logue, S.; Brennan, J.; Jiang, L.; Charych, E.; Egerland, U.; Liu, F.; Marquis, K. L.; Malamas, M.; Hage, T.; Comery, T. A.; Brandon, N. J. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive and negative symptoms of schizophrenia J. Pharmacol. Exp. Ther. 2009, 331, 574-590
9. Kehler, J.; Ritzén, A.; Greve, D. The potential therapeutic use of phosphodiesterase 10 inhibitors Expert Opin. Ther. Pat. 2007, 17, 147-158
10. Simpson, E. H.; Kellendonk, C.; Kandel, E. A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia Neuron 2010, 65, 585-596
11. Hebb, A. L.; Robertson, H. A. Role of phosphodiesterases in neurological and psychiatric disease Curr. Opin. Pharmacol. 2007, 7, 86-92
12. Menniti, F. S.; Faraci, W. S.; Schmidt, C. J. Phosphodiesterases in the CNS: targets for drug development Nature Rev. Drug Discovery 2006, 5, 661-670
13. Kleiman, R. J.; Kimmel, L. H.; Bove, S. E.; Lanz, T. A.; Harms, J. F.; Romegialli, A.; Miller, K. S.; Willis, A.; des Etages, S.; Kuhn, M.; Schmidt, C. J. Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntingont's Disease J. Pharmacol. Exp. Ther. 2011, 336, 64-76
14. Verhoest, P. T.; Chapin, D. S.; Corman, M.; Fonseca, K.; Harms, J. F.; Hou, X.; Marr, E. S.; Menniti, F. S.; Nelson, F.; O'Connor, R.; Pandit, J.; Proulx-LaFrance, C.; Schmidt, A. W.; Schmidt, C. J.; Suiciak, J. A.; Liras, S. J. Med. Chem. 2009, 52, 5188-5196
15. Chappie, T. A.; Humphrey, J. M.; Allen, M. P.; Estep, K. G.; Fox, C. B.; Lebel, L. A.; Liras, S.; Marr, E. S.; Menniti, F. S.; Pandit, J.; Schmidt, C. J.; Tu, M.; Williams, R. D.; Yang, F. V. Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors J. Med. Chem. 2007, 50, 182-185
16. Cantin, L.-D.; Magnuson, S.; Gunn, D.; Barucci, N.; Breuhaus, M.; Bullock, W. H.; Burke, J.; Claus, T. H.; Daly, M.; DeCarr, L.; Gore-Willse, A.; Hoover-Litty, H.; Kumarasinghe, E. S.; Li, Y.; Liang, S. X.; Livingston, J. N.; Lowinger, T.; MacDougall, M.; Ogutu, H. O.; Olague, A.; Otto-Morgan, R.; Schoenleber, R. W.; Tersteegen, A.; Wickens, P.; Zhang, Z.; Zhu, J.; Zhu, L.; Sweet, L. PDE10A inhibitors as insulin secretagogues Bioorg. Med. Chem. Lett. 2007, 17, 2869-2873
17. Höfgen, N.; Stange, H.; Schindler, R.; Lankau, H.-J.; Grunwald, C.; Langen, B.; Egerland, U.; Tremmel, P.; Pangalos, M. N.; Marquis, K. L.; Hage, T.; Harrison, B. L.; Malamas, M. S.; Brandon, N. J.; Kronbach, T. Discovery of imidazo[1,5-a ]pyrido[3,2-e ]pyrazines as a new class of phosphodiesterase 10A inhibitors J. Med. Chem. 2010, 53, 4399-4411
18. Kehler, J.; Ritzen, A.; Langgård, M.; Petersen, S. L.; Farah, M. M.; Bundgaard, C.; Christoffersen, C. T.; Nielsen, J.; Kilburn, J. P. Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 3738-3742
19. Helal, C. J.; Kang, Z.; Hou, X.; Pandit, J.; Chappie, T. A.; Humphrey, J. M.; Marr, E. S.; Fennell, K. F.; Chenard, L. K.; Fox, C.; Schmidt, C. J.; Williams, R. D.; Chapin, D. S.; Siuciak, J.; Lebel, L.; Menniti, F.; Cianfrongna, J.; Fonseca, K. R.; Nelson, F. R.; O'Connor, R.; MacDougall, M.; McDowell, L.; Liras, S. Use of structure-based design to discover a potent, selective, in vivo active phosphodiesterase 10A inhibitor lead series for the treatment of schizophrenia J. Med. Chem. 2011, 54, 4536-4547
20. Rzasa, R. M.; Hu, E.; Rumfelt, S.; Chen, N.; Andrews, K. L.; Chmait, S.; Falsey, J. R.; Zhong, W.; Jones, A. D.; Porter, A.; Louie, S. W.; Zhao, X.; Treanor, J. S.; Allen, J. R. Discovery of selective biaryl ethers as PDE10A inhibitors: improvement in potency and mitigation of Pgp-mediated efflux Bioorg. Med. Chem. Lett. 2012, 22, 7371-7375
21. Hu, E.; Kunz, R. K.; Rumfelt, S.; Chen, N.; Bürli, R.; Li, C.; Andrews, K. L.; Zhang, J.; Chmait, S.; Kogan, J.; Lindstrom, M.; Hitchcock, S. A.; Treanor, J. Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors Bioorg. Med. Chem. Lett. 2012, 22, 2262-2265
22. Hu, E.; Kunz, R. K.; Rumfelt, S.; Andrews, K. L.; Li, C.; Hitchcock, S. A.; Lindstrom, M.; Treanor, J. Use of structure based design to increase selectivity of pyridyl-cinnoline phosphodiesterase 10A (PDE10A) against phosphodiesterase 3 (PDE3) Bioorg. Med. Chem. Lett. 2012, 22, 6938-6942
23. Kehler, J.; Nielsen, J. PDE10A inhibitors: novel therapeutic drugs for schizophrenia Curr. Pharm. Des. 2011, 17, 137-150
24. Malamas, M. S.; Ni, Y.; Erdei, J.; Stange, H.; Schindler, R.; Lankau, H.-J.; Grunwald, C.; Fan, K. Y.; Parris, K.; Langen, B.; Egerland, U.; Hage, T.; Marquis, K. L.; Grauer, S.; Brennan, J.; Navarra, R.; Graf, R.; Harrison, B. L.; Robichaud, A.; Kronbach, T.; Pangalos, M. N.; Hoefgen, N.; Brandon, N. J. Highly potent, selective, and orally active phosphodiesterase 10A inhibitors J. Med. Chem. 2011, 54, 7621-7638
25. Banerjee, A.; Narayana, A.; Raje, F. A.; Pisal, D. V.; Kadam, P. A.; Gullapalli, S.; Kumar, H.; More, S. V.; Bajpai, M.; Sangana, R. R.; Jadhav, S.; Gudi, G. S.; Khairatkar-Joshi, N.; Merugu, R. R. T.; Voleti, S. R.; Gharat, L. A. Discovery of benzo[ d ]imidazo[5,1-b ]thiazole as a new class of phosphodiesterase 10A inhibitors Bioorg. Med. Chem. Lett. 2013, 23, 6747-6754
26. Conti, M.; Beavo, J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling Annu. Rev. Biochem. 2007, 76, 481-511
27. Schmidt, C. J.; Chapin, D. S.; Cianfrogna, J.; Corman, M. L.; Hajos, M.; Harms, J. F.; Hoffman, W. E.; Lebel, L. A.; McCarthy, S. A.; Nelson, F. R.; Proulx-LaFrance, C.; Majchrzak, M. J.; Ramirez, A. D.; Schmidt, K.; Seymour, P. A.; Siuciak, J. A.; Tingley, F. D., III; Williams, R. D.; Verhoest, P. R.; Menniti, F. S. Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia J. Pharmacol. Exp. Ther. 2008, 325, 681-690
28. Sotty, F.; Montezinho, L.; Steiniger-Brach, B.; Nielson, J. Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to d-amphetamine: involvement of the D1-regulated feedback control of midbrain dopamine neurons J. Neurochem. 2009, 109, 766-775
29. Miyamoto, S.; Duncan, G. E.; Marx, C. E.; Lieberman, J. A. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs Mol. Psychiatry 2005, 10, 79-104
30. Bender, A. T.; Beavo, J. A. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use Pharmacol. Rev. 2006, 58, 488-520
31. Wadenberg, M.; Soliman, A.; VanderSpek, S. C.; Kapur, S. Dopamine D2 Receptor Occupancy Is a Common Mechanism Underlying Animal Models of Antipsychotics and Their Clinical Effects Neuropsycopharmacology 2001, 25, 633-641
32. Rowley, M.; Bristow, L. J.; Hutson, P. H. Current and novel approaches to the drug treatment of schizophrenia J. Med. Chem. 2001, 44, 477-501
33. Miyamoto, S.; Duncan, G. E.; Marx, C. E.; Lieberman, J. A. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs Mol. Psychiatry 2005, 10, 79-104
34. Hu, E.; Kunz, R. K.; Chen, N.; Rumfelt, S.; Siegmund, A.; Andrews, K.; Chmait, S.; Zhao, S.; Davis, C.; Chen, H.; Lester-Zeiner, D.; Ma, J.; Biorn, C.; Shi, J.; Porter, A.; Treanor, J.; Allen, J. R. Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A) J. Med. Chem. 2013, 56, 8781-8792
35. Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.; Reider, R. J. New air-stable catalysts for general and efficient Suzuki-Miyaura cross-coupling reactions of heteroaryl chlorides Org. Lett. 2006, 8, 1787-1789
36. Corley, E. G.; Conrad, K.; Murry, J. A.; Savarin, C.; Holko, J.; Boice, G. Direct synthesis of 4-arylpiperidines via palladium/copper(I)-cocatalyzed Negishi coupling of a 4-piperidylzinc iodide with aromatic halides and triflates J. Org. Chem. 2004, 69, 5120-5123
37. Hu, E.; Ma, J.; Biorn, C.; Lester-Zeiner, D.; Cho, R.; Rumfelt, S.; Kunz, R. K.; Nixey, T.; Michelsen, K.; Miller, S.; Shi, J.; Wong, J.; Della Puppa, G. H.; Able, J.; Talreja, S.; Hwang, D.-H.; Hitchcock, S. A.; Porter, A.; Immke, D.; Allen, J. R.; Treanor, J.; Chen, H. Rapid identification of a novel small molecule phosphodiesterase 10A (PDE10A) tracer J. Med. Chem. 2012, 55, 4776-4787
38. Morenal, J. L.; González-Maeso, J. Preclinical models of antipsychotic drug action Int. J. Neuropsychopharmacol. 2013, 16, 2131-2144