Design and synthesis of tricyclic imidazo[4,5-b]pyridin-2-ones as corticotropin-releasing factor-1 antagonists

  • J Med Chem. 2005 Aug 11;48(16):5104-7. doi: 10.1021/jm050384+.
Zhiqiang Guo  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. [email protected]
PMID: 16078829 DOI: 10.1021/jm050384+
Abstract

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.