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.

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Wu YJ, Davis CD, Dworetzky S, Fitzpatrick WC, Harden D, He H, Knox RJ, Newton AE, Philip T, Polson C, Sivarao DV, Sun LQ, Tertyshnikova S, Weaver D, Yeola S, Zoeckler M, Sinz MW

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.

J Med Chem. 2003 Aug 28;46(18):3778-81.

PubMed ID
12930139 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
TroleandomycinCytochrome P450 3A4IC 50 (nM)61000N/AN/ADetails
TroleandomycinCytochrome P450 3A4IC 50 (nM)33000N/AN/ADetails
TroleandomycinCytochrome P450 3A4IC 50 (nM)16000N/AN/ADetails
TroleandomycinCytochrome P450 3A4IC 50 (nM)20000N/AN/ADetails