title: The discovery and synthesis of potent zwitterionic inhibitors of renin.
abstract: The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. renee.aspiotis@sympatico.ca
authors.forename: Renee
authors.initials: R
authors.lastname: Aspiotis
authors.forename: Austin
authors.initials: A
authors.lastname: Chen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cauchon
authors.forename: Daniel
authors.initials: D
authors.lastname: Dubé
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gagné
authors.forename: Michel
authors.initials: M
authors.lastname: Gallant
authors.forename: Erich L
authors.initials: EL
authors.lastname: Grimm
authors.forename: Robert
authors.initials: R
authors.lastname: Houle
authors.forename: Hélène
authors.initials: H
authors.lastname: Juteau
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: Dwight
authors.initials: D
authors.lastname: MacDonald
authors.forename: Dan
authors.initials: D
authors.lastname: McKay
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Patrick
authors.initials: P
authors.lastname: Roy
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Soisson
authors.forename: Tom
authors.initials: T
authors.lastname: Wu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D020134:Catalytic Domain; D003198:Computer Simulation; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D010880:Piperidines; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors