Design and synthesis of tricyclic imidazo[4,5-b]pyridin-2-ones as corticotropin-releasing factor-1 antagonists.
Journal of medicinal chemistry 2005 Aug 11; 48(16):5104-7
Guo Z Z, Tellew J JE, Gross R RS, Dyck B B, Grey J J, Haddach M M, Kiankarimi M M, Lanier M M, Li B BF, Luo Z Z, McCarthy J JR, Moorjani M M, Saunders J J, Sullivan R R, Zhang X X, Zamani-Kord S S, Grigoriadis D DE, Crowe P PD, Chen T TK, Williams J JP
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. zguo@neurocrine.com
The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.