Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors.
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.
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195-7610, USA.
Hisashi
H
Suzuki
M Byron
MB
Kneller
Dan A
DA
Rock
Jeffrey P
JP
Jones
William F
WF
Trager
Allan E
AE
Rettie
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001463:Barbiturates / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D015195:Drug Design; D004789:Enzyme Activation; D006827:Hydantoins / Q000737:chemistry*; D008617:Mephenytoin / Q000031:analogs & derivatives* / Q000737:chemistry*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D010634:Phenobarbital / Q000737:chemistry*; D010672:Phenytoin / Q000031:analogs & derivatives / Q000737:chemistry*; D011485:Protein Binding
D001463:Barbiturates; D006827:Hydantoins; C014544:ethylphenylhydantoin; D010672:Phenytoin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin; D010634:Phenobarbital