Referenced in: none

Automatically associated channels: Kv7.2

Title: Fluorine substitution can block CYP3A4 metabolism-dependent inhibition: identification of (S)-N-[1-(4-fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an orally bioavailable KCNQ2 opener devoid of CYP3A4 metabolism-dependent inhibiti

Authors: Yong-Jin Wu, Carl D Davis, Steven Dworetzky, William C Fitzpatrick, David Harden, Huan He, Ronald J Knox, Amy E Newton, Thomas Philip, Craig Polson, Digavalli V Sivarao, Li-Qiang Sun, Svetlana Tertyshnikova, David Weaver, Suresh Yeola, Mary Zoeckler, Michael W Sinz

Journal, date & volume: J. Med. Chem., 2003 Aug 28 , 46, 3778-81

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12930139

Abstract
The formation of a reactive intermediate was found to be responsible for CYP3A4 metabolism-dependent inhibition (MDI) observed with (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenyl-acrylamide (1). Structure-3A4 MDI relationship studies culminated in the discovery of a difluoro analogue, (S)-N-[1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl]-3-(4-fluoro-phenyl)acrylamide (2), as an orally bioavailable KCNQ2 opener free of CYP3A4 MDI.