title: Renin inhibitors for the treatment of hypertension: design and optimization of a novel series of spirocyclic piperidines.
abstract: The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort 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: Renee
authors.initials: R
authors.lastname: Aspiotis
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cauchon
authors.forename: Amadine
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: Yongxin
authors.initials: Y
authors.lastname: Han
authors.forename: Robert
authors.initials: R
authors.lastname: Houle
authors.forename: Sébastien
authors.initials: S
authors.lastname: Laliberté
authors.forename: Guillaume
authors.initials: G
authors.lastname: Larouche
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
authors.forename: Dan
authors.initials: D
authors.lastname: McKay
authors.forename: David
authors.initials: D
authors.lastname: Percival
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D015195:Drug Design; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008253:Macaca mulatta; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D012083:Renin / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000959:Antihypertensive Agents; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D010880:Piperidines; D011480:Protease Inhibitors; D012083:Renin; D013141:Spiro Compounds; D000092502:Renin Inhibitors; C510163:CYP3A4 protein, human