title: Renin inhibitors for the treatment of hypertension: design and optimization of a novel series of pyridone-substituted piperidines.
abstract: An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1. austin.chihyu.chen@gmail.com
authors.forename: Austin
authors.initials: A
authors.lastname: Chen
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cauchon
authors.forename: Amandine
authors.initials: A
authors.lastname: Chefson
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Daniel
authors.initials: D
authors.lastname: Dubé
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Fournier
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: Jing-Qi
authors.initials: JQ
authors.lastname: Huang
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacombe
authors.forename: Sébastien
authors.initials: S
authors.lastname: Laliberté
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
authors.forename: Susana
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: Dan
authors.initials: D
authors.lastname: McKay
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Chris
authors.initials: C
authors.lastname: Regan
authors.forename: Hillary
authors.initials: H
authors.lastname: Regan
authors.forename: René
authors.initials: R
authors.lastname: St-Jacques
authors.forename: Sylvie
authors.initials: S
authors.lastname: Toulmond
mesh_terms: D000818:Animals; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D011728:Pyridones; D000092502:Renin Inhibitors