title: Design and synthesis of potent, isoxazole-containing renin inhibitors.
abstract: The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada. pierre-andre_fournier@merck.com
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Fournier
authors.forename: Mélissa
authors.initials: M
authors.lastname: Arbour
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cauchon
authors.forename: Austin
authors.initials: A
authors.lastname: Chen
authors.forename: Amandine
authors.initials: A
authors.lastname: Chefson
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gagné
authors.forename: Erich
authors.initials: E
authors.lastname: Grimm
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
authors.forename: Robert
authors.initials: R
authors.lastname: Houle
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacombe
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
authors.forename: Dwight
authors.initials: D
authors.lastname: MacDonald
authors.forename: Bruce
authors.initials: B
authors.lastname: Mackay
authors.forename: Dan
authors.initials: D
authors.lastname: McKay
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Yeeman
authors.initials: Y
authors.lastname: Ramtohul
authors.forename: René
authors.initials: R
authors.lastname: St-Jacques
authors.forename: Sylvie
authors.initials: S
authors.lastname: Toulmond
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000959:Antihypertensive Agents; D007555:Isoxazoles; D000092502:Renin Inhibitors