Design and Synthesis of Tricyclic Imidazo[4,5-b]pyridin-2-ones as Corticotropin-Releasing Factor-1 Antagonists
journal contributionposted on 11.08.2005, 00:00 authored by Zhiqiang Guo, John E. Tellew, Raymond S. Gross, Brian Dyck, Jonathan Grey, Mustapha Haddach, Mehrak Kiankarimi, Marion Lanier, Bin-Feng Li, Zhiyong Luo, James R. McCarthy, Manisha Moorjani, John Saunders, Robert Sullivan, Xiaohu Zhang, Said Zamani-Kord, Dimitri E. Grigoriadis, Paul D. Crowe, Ta Kung Chen, John P. Williams
The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF1) 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 CRF1 antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.