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