Discovery of N-benzyl-2-[(4S)-4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5- dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6-yl]-N-isopropylacetamide, an orally active, gut-selective CCK1 receptor agonist for the potential treatment of obesity

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 22, 2010, Pages 6797-6801

  Elliott, Richard L ^a   Cameron, Kimberly O ^a   Chin, Janice E ^a   Bartlett, Jeremy A ^a   Beretta, Elena E ^a   Chen, Yue ^a   Jardine, Paul Da Silva ^a   Dubins, Jeffrey S ^a   Gillaspy, Melissa L ^a   Hargrove, Diane M ^a   Kalgutkar, Amit S ^a   Laflamme, Janet A ^a   Lame, Mary E ^a   Martin, Kelly A ^a   Maurer, Tristan S ^a   Nardone, Nancy A ^a   Oliver, Robert M ^a   Scott, Dennis O ^a   Sun, Dexue ^a   Swick, Andrew G ^a   Trebino, Catherine E ^a   Zhang, Yingxin ^a   more..

^a PFIZER INC   (United States)

Author keywords

CCK; CCK1R; Cholecystokinin; Gut selective; Triazolobenzodiazepinone

Indexed keywords

BENZODIAZEPINE DERIVATIVE; CHOLECYSTOKININ A RECEPTOR; GI 181771 X; HEMOGLOBIN A1C; SR 146131; UNCLASSIFIED DRUG;

ALKYLATION; ANIMAL EXPERIMENT; ARTICLE; BODY WEIGHT; DRUG DESIGN; DRUG EFFICACY; DRUG STRUCTURE; DRUG SYNTHESIS; FEEDING; FOOD INTAKE; GALLBLADDER; IC 50; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; OBESITY; RAT; SPRAGUE DAWLEY RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-OBESITY AGENTS; BENZODIAZEPINES; MALE; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, CHOLECYSTOKININ; STRUCTURE-ACTIVITY RELATIONSHIP;

RODENTIA;

EID: 77958055298     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.08.115     Document Type: Article

References (34)

1. T.J. Little, M. Horowitz, and C. Feinle-Bisset Obes. Rev. 6 2005 297
2. R.A. Liddle, I.D. Goldfine, M.S. Rosen, R.A. Taplitz, and J.A. Williams J. Clin. Invest. 75 1985 1144
3. F. Noble, S.A. Wank, J.N. Crawley, J. Bradwejn, K.B. Seroogy, M. Hamon, and B.P. Roques Pharmacol. Rev. 51 1999 745
4. H. Wang, P.T.-H. Wong, J. Spiess, and Y.Z. Zhu Neurosci. Biobehav. Rev. 29 2005 1361
5. R. Herranz Med. Res. Rev. 23 2003 559
6. J.R. Szewczyk, and C. Laudeman Curr. Top. Med. Chem. 8 2003 8837
7. A.I. Sayegh, J.R. Reeve Jr., S.T. Lampley, B. Hart, S. Gulley, A.R. Esdaile, S.K. Sharma, T. Webb, C.S. Williams, and F. Pruitt J. Am. Vet. Med. Assoc. 226 2005 1809
8. A.I. Sayegh, and R.C. Ritter Peptides 24 2003 237
9. T.H. Moran, and K.P. Kinzig Am. J. Physiol. 286 2004 G183
10. T.H. Moran Physiol. Behav. 82 2004 175
11. M.J. Berna, and R.T. Jensen Curr. Top. Med. Chem. 7 2007 1211
12. B. Ahren, J.J. Holst, and S. Efendic J. Clin. Endocrinol. Metab. 85 2000 1043
13. G.C. Hirst, C. Aquino, L. Birkemo, D.K. Croom, M. Dezube, R.W. Dougherty Jr., G.N. Ervin, M.K. Grizzle, B. Henke, M.K. James, M.F. Johnson, T. Momtahen, K.L. Queen, R.G. Sherrill, J. Szewczyk, T.M. Willson, and E.E. Sugg J. Med. Chem. 39 1996 5236
14. C.J. Aquino, D.R. Armour, J.M. Berman, L.S. Birkemo, R.A. Carr, D.K. Croom, M. Dezube, R.W. Dougherty Jr., G.N. Ervin, M.K. Grizzle, J.E. Head, G.C. Hirst, M.K. James, M.F. Johnson, L.J. Miller, K.L. Queen, T.J. Rimele, D.N. Smith, and E.E. Sugg J. Med. Chem. 39 1996 562
15. E.E. Sugg, L. Birkemo, L.S. Gan, and T.K. Tippin Pharm. Biotechnol. 11 1998 507
16. E. Bignon, A. Bachy, R. Boigegrain, R. Brodin, M. Cottineau, D. Gully, J.M. Herbert, P. Keane, C. Labie, J.C. Mollimard, D. Olliero, F. Oury-Donat, C. Petereau, V. Prabonnaud, M.P. Rockstroh, P. Schaeffer, O. Servant, O. Thurneyssen, P. Soubrié, M. Pascal, J.P. Maffrand, and G. Le Fur J. Pharmacol. Exp. Ther. 289 1999 742
17. C. Zhu, A.R. Hansen, T. Bateman, Z. Chen, T.G. Holt, J.A. Hubert, B.V. Karanam, S.J. Lee, J. Pan, S. Qian, V.B. Reddy, M.L. Reitman, A.M. Strack, V. Tong, D.T. Weingarth, M.S. Wolff, D.J. MacNeil, A.E. Weber, J.L. Duffy, and S.D. Edmondson Bioorg. Med. Chem. Lett. 8 2008 4393
18. E.J. Castillo, S. Delgado-Aros, M. Camilleri, D. Burton, D. Stephans, R. O'Connor-Semmes, A. Walker, A. Shachoy-Clark, and A.R. Zinsmeister Am. J. Physiol. Gastrointest. Liver Physiol. 287 2004 G363
19. J. Jordon, F.L. Greenway, L.A. Leiter, Z. Li, P. Jacobson, K. Murphy, J. Hill, L. Kler, and R.P. Aftring Clin. Pharmacol. Ther. 83 2008 281
20. A.D. Roses Clin. Pharmacol. Ther. 85 2009 362
21. Additional details regarding pharmacology and clinical trial results of 4a will be reported in future publications.
22. C.A. Lipinski, F. Lombardo, B.W. Dominy, and P.J. Feeney Adv. Drug Delivery Rev. 46 2001 3
23. Elliott, R. L.; Cameron, K. O.; Hammond, M. U.S. Patent 7,358,242, 2005.
24. Stereochemistry at C-3 for the active enantiomer 4a was determined to be in the S configuration based on the following experiment: (1) single X-ray analysis of N-benzyl-2-{(4S)-4-[(5-bromo-1H-indol-3-yl)methyl]-5-oxo-1-phenyl-4, 5-dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6-yl}-N- isopropylacetamide; (2) removal of bromide via hydrogenation provided 4a. The crystal structure has been deposited at the Cambridge Crystallographic Data Centre and was allocated the following deposition number: CCDC 789675.
25. B.E. Evans, M.G. Bock, K.E. Rittle, R.M. DiPardo, W.L. Whitter, D.F. Veber, P.S. Anderson, and R.M. Freidinger Proc. Natl. Acad. Sci. U.S.A. 83 1986 4918
26. B.R. Henke, C.J. Aquino, L.S. Birkemo, D.K. Croom, R.W. Dougherty Jr., G.N. Ervin, M.K. Grizzle, G.C. Hirst, M.K. James, M.F. Johnson, K.L. Queen, R.G. Sherrill, E.E. Sugg, E.M. Suh, J.W. Szewczyk, R.J. Unwalla, J. Yingling, and T.M. Willson J. Med. Chem. 40 1997 2706
27. 2b CCK2R stimulation was evaluated for 4a and 4g in a calcium mobilization assay (FLIPR) while CCK2R inhibition was examined by GTPγ35S binding. Compounds 4a and 4g had no significant activity at 10,000 nM in either assay. A full account of the triazolobenzodiazepinone SAR will be published in a separate manuscript.
28. F. Makovec, M. Bani, R. Cereda, R. Christe, M.A. Pacini, L. Revel, and L.C. Rovati Pharmacol. Res. Commun. 19 1987 41
29. An oral dose of amorphous 4a at 6 mg/kg produced a 44% reduction in food intake at 4 h relative to vehicle (P <0.05) while an oral dose of 6 mg/kg of 4a with 20 mg/kg of the CCK1R antagonist, Lorglumide, resulted in a non-significant change (2.4%) in food intake relative to vehicle, suggesting that the observed decreases in food intake are mediated by the CCK1R mechanism.
30. Compound 4a was formulated as a 25 wt % drug: 75 wt % hydroxypropyl methylcellulose acetate succinate-high granular (HPMCAS-HG) SDD in 0.5% methylcellulose.
31. N. Rasenack, and B.W. Müller Pharm. Res. 19 2002 1894
32. D.T. Friesen, R. Shanker, M. Crew, D.T. Smithey, W.J. Curatolo, and J.A.S. Nightingale Mol. Pharm. 5 2008 1003
33. W. Curatolo, J.A. Nightingale, and S.M. Herbig Pharm. Res. 26 2009 1419
34. R.S. Obach Drug Metab. Dispos. 27 1999 1350