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 inhibition.

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 OF MEDICINAL CHEMISTRY（2003）

Cited 65|Views4

No score

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.

Translated text

Key words

bioavailable kcnq2 opener devoid,metabolism-dependent,metabolism-dependent

AI Read Science

Must-Reading Tree

Example

Generate MRT to find the research sequence of this paper

Chat Paper

Summary is being generated by the instructions you defined