Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors

Hisashi Suzuki; M Byron Kneller; Dan A Rock; Jeffrey P Jones; William F Trager; Allan E Rettie

doi:10.1016/j.abb.2004.05.015

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Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors

Journal article

Peer reviewed

Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors

Hisashi Suzuki, M Byron Kneller, Dan A Rock, Jeffrey P Jones, William F Trager and Allan E Rettie

Archives of biochemistry and biophysics, Vol.429(1), pp.1-15

09/01/2004

DOI: https://doi.org/10.1016/j.abb.2004.05.015

Handle:

https://hdl.handle.net/2376/112641

PMID: 15288804

Abstract

Cytochrome P-450 CYP2C9

Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors

Models, Chemical

Mephenytoin - analogs & derivatives

Models, Molecular

Phenytoin - analogs & derivatives

Mixed Function Oxygenases - antagonists & inhibitors

Mixed Function Oxygenases - chemistry

Phenytoin - chemistry

Barbiturates - chemistry

Cytochrome P-450 CYP2C19

Mephenytoin - chemistry

Computer Simulation

Drug Design

Protein Binding

Enzyme Activation

Phenobarbital - chemistry

Hydantoins - chemistry

Aryl Hydrocarbon Hydroxylases - chemistry

Binding Sites

Three series of N-3 alkyl substituted phenytoin, nirvanol, and barbiturate derivatives were synthesized and their inhibitor potencies were tested against recombinant CYP2C19 and CYP2C9 to probe the interaction of these ligands with the active sites of these enzymes. All compounds were found to be competitive inhibitors of both enzymes, although the degree of inhibitory potency was generally much greater towards CYP2C19. Inhibitor stereochemistry did not markedly influence K(i) towards CYP2C9, and log P adequately predicted inhibitor potency for this enzyme. In contrast, stereochemistry was an important factor in determining inhibitor potency towards CYP2C19. (S)-(+)-N-3-Benzylnirvanol and (R)-(-)-N-3-benzylphenobarbital emerged as the most potent and selective CYP2C19 inhibitors, with K(i) values of < 250nM--at least two orders of magnitude greater inhibitor potency than towards CYP2C9. Both inhibitors were metabolized preferentially at their C-5 phenyl substituents, indicating that CYP2C19 prefers to orient the N-3 substituents away from the active oxygen species. These features were incorporated into expanded CoMFA models for CYP2C9, and a new, validated CoMFA model for CYP2C19.

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Title: Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors
Creators: Hisashi Suzuki - Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195-7610, USA
M Byron Kneller
Dan A Rock
Jeffrey P Jones
William F Trager
Allan E Rettie
Publication Details: Archives of biochemistry and biophysics, Vol.429(1), pp.1-15
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: GM 32165 / NIGMS NIH HHS
Identifiers: 99900548071101842
Language: English
Resource Type: Journal article

Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors

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