| Literature DB >> 19552436 |
Richard A Hartz1, Vijay T Ahuja, Maria Rafalski, William D Schmitz, Allison B Brenner, Derek J Denhart, Jonathan L Ditta, Jeffrey A Deskus, Eddy W Yue, Argyrios G Arvanitis, Snjezana Lelas, Yu-Wen Li, Thaddeus F Molski, Harvey Wong, James E Grace, Kimberley A Lentz, Jianqing Li, Nicholas J Lodge, Robert Zaczek, Andrew P Combs, Richard E Olson, Ronald J Mattson, Joanne J Bronson, John E Macor.
Abstract
A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. Selected compounds proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, we describe an in vitro intrinsic clearance-based approach to the optimization of pyrazinone-based CRF(1) receptor antagonists wherein sites of metabolism were identified by incubation with human liver microsomes. It was found that the rate of metabolism could be decreased by incorporation of appropriate substituents at the primary sites of metabolism. This led to the discovery of compound 12x, a highly potent (IC(50) = 1.0 nM) and selective CRF(1) receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.Entities:
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Year: 2009 PMID： 19552436 DOI： 10.1021/jm900302q
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446