title: Addressing time-dependent CYP 3A4 inhibition observed in a novel series of substituted amino propanamide renin inhibitors, a case study.
abstract: Time-dependent inhibitors of CYPs have the potential to perpetrate drug-drug interactions in the clinical setting. After finding that several leading compounds in a novel series of substituted amino propanamide renin inhibitors inactivated CYP3A4 in an NADPH-dependent and time-dependent manner, a search to identify the cause of this liability was initiated. Extensive SAR revealed that the amide bridge present in compound 1 as a possible culprit. Through the installation of a metabolic soft spot distal to this moiety, potent renin inhibitors with improved CYP profile were identified.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada. austin_chen@merck.com
authors.forename: Austin
authors.initials: A
authors.lastname: Chen
authors.forename: Daniel
authors.initials: D
authors.lastname: Dubé
authors.forename: Laurence
authors.initials: L
authors.lastname: Dubé
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gagné
authors.forename: Michel
authors.initials: M
authors.lastname: Gallant
authors.forename: Mireille
authors.initials: M
authors.lastname: Gaudreault
authors.forename: Erich
authors.initials: E
authors.lastname: Grimm
authors.forename: Robert
authors.initials: R
authors.lastname: Houle
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacombe
authors.forename: Sébastien
authors.initials: S
authors.lastname: Laliberté
authors.forename: Suzanna
authors.initials: S
authors.lastname: Liu
authors.forename: Dwight
authors.initials: D
authors.lastname: MacDonald
authors.forename: Bruce
authors.initials: B
authors.lastname: Mackay
authors.forename: David
authors.initials: D
authors.lastname: Martin
authors.forename: Dan
authors.initials: D
authors.lastname: McKay
authors.forename: David
authors.initials: D
authors.lastname: Powell
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
mesh_terms: D000577:Amides / Q000737:chemistry; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011422:Propionates / Q000737:chemistry*; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D011422:Propionates; D000092502:Renin Inhibitors; C510163:CYP3A4 protein, human