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.
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.
Wu
Yong-Jin
YJ
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA. yong-jin.wu@bms.com
Davis
Carl D
CD
Dworetzky
Steven
S
Fitzpatrick
William C
WC
Harden
David
D
He
Huan
H
Knox
Ronald J
RJ
Newton
Amy E
AE
Philip
Thomas
T
Polson
Craig
C
Sivarao
Digavalli V
DV
Sun
Li-Qiang
LQ
Tertyshnikova
Svetlana
S
Weaver
David
D
Yeola
Suresh
S
Zoeckler
Mary
M
Sinz
Michael W
MW
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D002934:Cinnamates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004195:Disease Models, Animal; D005461:Fluorine / Q000737:chemistry*; D007275:Injections, Intravenous; D015640:Ion Channel Gating; D051658:KCNQ2 Potassium Channel; D008297:Male; D008564:Membrane Potentials; D008881:Migraine Disorders / Q000188:drug therapy / Q000503:physiopathology; D009025:Morpholines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010296:Parietal Lobe / Q000187:drug effects / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002934:Cinnamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D051658:KCNQ2 Potassium Channel; C496915:Kcnq2 protein, rat; D009025:Morpholines; C477185:N-(1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl)-3-(4-fluorophenyl)acrylamide; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D005461:Fluorine; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human