Design and Synthesis of Tricyclic
Imidazo[4,5-b]pyridin-2-ones as
Corticotropin-Releasing Factor-1
Antagonists

Guo, Zhiqiang; Tellew, John E.; Gross, Raymond S.; Dyck, Brian; Grey, Jonathan; Haddach, Mustapha; Kiankarimi, Mehrak; Lanier, Marion; Li, Bin-Feng; Luo, Zhiyong; McCarthy, James R.; Moorjani, Manisha; Saunders, John; Sullivan, Robert; Zhang, Xiaohu; Zamani-Kord, Said; Grigoriadis, Dimitri E.; Crowe, Paul D.; Chen, Ta Kung; Williams, John P.

doi:10.1021/jm050384+.s001

jm050384+_si_001.pdf (147.04 kB)

Design and Synthesis of Tricyclic Imidazo[4,5-b]pyridin-2-ones as Corticotropin-Releasing Factor-1 Antagonists

journal contribution

posted 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.