title: Ligand-based design of a potent and selective inhibitor of cytochrome P450 2C19.
abstract: A series of omeprazole-based analogues was synthesized and assessed for inhibitory activity against CYP2C19. The data was used to build a CYP2C19 inhibition pharmacophore model for the series. The model was employed to design additional analogues with inhibitory potency against CYP2C19. Upon identifying inhibitors of CYP2C19, ligand-based design shifted to attenuating the rapid clearance observed for many of the inhibitors. While most analogues underwent metabolism on their aliphatic side chain, metabolite identification indicated that for analogues such as compound 30 which contain a heterocycle adjacent to the sulfur moiety, metabolism primarily occurred on the benzimidazole moiety. Compound 30 exhibited improved metabolic stability (Cl(int) = 12.4 mL/min/nmol) and was selective in regard to inhibition of CYP2C19-catalyzed (S)-mephenytoin hydroxylation in human liver microsomes. Finally, representative compounds were docked into a homology model of CYP2C19 in an effort to understand the enzyme-ligand interactions that may lead to favorable inhibition or metabolism properties.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington 98119, United States.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Foti
authors.forename: Dan A
authors.initials: DA
authors.lastname: Rock
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Han
authors.forename: Robert A
authors.initials: RA
authors.lastname: Flowers
authors.forename: Larry C
authors.initials: LC
authors.lastname: Wienkers
authors.forename: Jan L
authors.initials: JL
authors.lastname: Wahlstrom
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain; D065731:Cytochrome P-450 CYP2C19; D015195:Drug Design; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008024:Ligands; D008617:Mephenytoin / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin