title: In vitro intrinsic clearance-based optimization of N3-phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists.
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.
authors: Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, USA. richard.hartz@bms.com
authors: Richard A
authors: RA
authors: Hartz
authors: Vijay T
authors: VT
authors: Ahuja
authors: Maria
authors: M
authors: Rafalski
authors: William D
authors: WD
authors: Schmitz
authors: Allison B
authors: AB
authors: Brenner
authors: Derek J
authors: DJ
authors: Denhart
authors: Jonathan L
authors: JL
authors: Ditta
authors: Jeffrey A
authors: JA
authors: Deskus
authors: Eddy W
authors: EW
authors: Yue
authors: Argyrios G
authors: AG
authors: Arvanitis
authors: Snjezana
authors: S
authors: Lelas
authors: Yu-Wen
authors: YW
authors: Li
authors: Thaddeus F
authors: TF
authors: Molski
authors: Harvey
authors: H
authors: Wong
authors: James E
authors: JE
authors: Grace
authors: Kimberley A
authors: KA
authors: Lentz
authors: Jianqing
authors: J
authors: Li
authors: Nicholas J
authors: NJ
authors: Lodge
authors: Robert
authors: R
authors: Zaczek
authors: Andrew P
authors: AP
authors: Combs
authors: Richard E
authors: RE
authors: Olson
authors: Ronald J
authors: RJ
authors: Mattson
authors: Joanne J
authors: JJ
authors: Bronson
authors: John E
authors: JE
authors: Macor
mesh_terms: D000818:Animals; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008657:Metabolic Clearance Rate; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D011719:Pyrazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1