Discovery of substituted biphenyl imidazoles as potent, bioavailable bombesin receptor subtype-3 agonists

Extensive SAR studies of a series derived from RY-337, a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead, led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3. Analogs in this series demonstrated good rat pharmacokinetics. We rep...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 20; no. 6; pp. 1913 - 1917
Main Authors:	He, Shuwen, Dobbelaar, Peter H., Liu, Jian, Jian, Tianying, Sebhat, Iyassu K., Lin, Linus S., Goodman, Allan, Guo, Cheng, Guzzo, Peter R., Hadden, Mark, Henderson, Alan J., Ruenz, Megan, Sargent, Bruce J., Yet, Larry, Kelly, Theresa M., Palyha, Oksana, Kan, Yanqing, Pan, Jie, Chen, Howard, Marsh, Donald J., Shearman, Lauren P., Strack, Alison M., Metzger, Joseph M., Feighner, Scott D., Tan, Carina, Howard, Andrew D., Tamvakopoulos, Constantin, Peng, Qianping, Guan, Xiao-Ming, Reitman, Marc L., Patchett, Arthur A., Wyvratt, Matthew J., Nargund, Ravi P.
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 15-03-2010 Elsevier
Subjects:	Agonist Animals Biological and medical sciences Biological Availability Biphenyl imidazole Bombesin receptor subtype-3 BRS3 Drug Discovery General and cellular metabolism. Vitamins Humans Imidazoles - chemistry Imidazoles - pharmacokinetics Imidazoles - pharmacology Medical sciences Pharmacology. Drug treatments Rats Receptors, Bombesin - agonists Structure-Activity Relationship Agonist Bombesin receptor subtype-3 Biphenyl imidazole BRS3 Human Imidazole derivatives Obesity Rodentia Bioavailability In vitro Biological activity In vivo Vertebrata Mammalia Biphenyl derivatives Intracerebral administration Pharmacokinetics BB3 bombesin receptor
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Summary:	Extensive SAR studies of a series derived from RY-337, a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead, led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3. Analogs in this series demonstrated good rat pharmacokinetics. We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.01.154