title: Design and optimization of a substituted amino propanamide series of renin inhibitors for the treatment of hypertension.
abstract: The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1. austin_chen@merck.com
authors.forename: Austin
authors.initials: A
authors.lastname: Chen
authors.forename: Christopher
authors.initials: C
authors.lastname: Bayly
authors.forename: Olivier
authors.initials: O
authors.lastname: Bezençon
authors.forename: Sylvia
authors.initials: S
authors.lastname: Richard-Bildstein
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: Jean-François
authors.initials: JF
authors.lastname: Lévesque
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: L'ubos
authors.initials: L
authors.lastname: Remen
authors.forename: Stephen
authors.initials: S
authors.lastname: Soisson
authors.forename: Sylvie
authors.initials: S
authors.lastname: Toulmond
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000959:Antihypertensive Agents; D012083:Renin; D000092502:Renin Inhibitors