Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A)

Journal of Medicinal Chemistry

Volumn 56, Issue 21, 2013, Pages 8781-8792

  Hu, Essa ^a   Kunz, Roxanne K ^a   Chen, Ning ^a   Rumfelt, Shannon ^a   Siegmund, Aaron ^a   Andrews, Kristin ^a   Chmait, Samer ^a   Zhao, Sharon ^a   Davis, Carl ^a   Chen, Hang ^a   Lester Zeiner, Dianna ^a   Ma, Ji ^a   Biorn, Christopher ^a   Shi, Jianxia ^a   Porter, Amy ^a   Treanor, James ^a   Allen, Jennifer R ^a  

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZIMIDAZOLE; BENZIMIDAZOLE DERIVATIVE; CARBONYL DERIVATIVE; KETOBENZIMIDAZOLE; MULTIDRUG RESISTANCE PROTEIN; PHOSPHODIESTERASE 10A INHIBITOR; PHOSPHODIESTERASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BRAIN HOMOGENATE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFICACY; DRUG POTENCY; DRUG SCREENING; ENZYME ACTIVE SITE; HIGH THROUGHPUT SCREENING; HYDROGEN BOND; IN VITRO STUDY; IN VIVO STUDY; LIQUID CHROMATOGRAPHY; MALE; MASS SPECTROMETRY; NONHUMAN; RAT; RECEPTOR OCCUPANCY;

ANIMALS; BENZIMIDAZOLES; CELLS, CULTURED; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; HUMANS; KETONES; MALE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; SWINE;

EID: 84887882340     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401234w     Document Type: Article

References (19)

1. 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
2. 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
3. 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
4. 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
5. 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
6. Kehler, J.; Ritzén, A.; Greve, D. R. The potential therapeutic use of phosphodiesterase 10 inhibitors Expert Opin. Ther. Pat. 2007, 17, 147-158
7. 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
8. Kehler, J.; Ritzen, A.; LanggaÌŠrd, 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. Conti, M.; Beavo, J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling Annu. Rev. Biochem. 2007, 76, 481-511
15. 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
16. Hitchcock, S. A.; Pennington, L. D. Structure-brain exposure relationships J. Med. Chem. 2006, 49, 7559-7583
17. 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
18. Wang, H.; Liu, Y.; Hou, J.; Zheng, M.; Robinson, H.; Ke, H. Structural insight into substrate specificity of phosphodiesterase 10 Proc. Nat. Acad. Sci. U. S. A. 2007, 104, 5782-5787
19. Schinkel, A. H.; Wagenaar, E.; van Deemter, L.; Mol, C. A. A. M.; Borst, P. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A J. Clin. Invest. 1995, 96, 1698-1705