title: Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors.
abstract: A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48106-1047.
authors.forename: A M
authors.initials: AM
authors.lastname: Doherty
authors.forename: I
authors.initials: I
authors.lastname: Sircar
authors.forename: B E
authors.initials: BE
authors.lastname: Kornberg
authors.forename: J
authors.initials: J
authors.lastname: Quin
authors.forename: R T
authors.initials: RT
authors.lastname: Winters
authors.forename: J S
authors.initials: JS
authors.lastname: Kaltenbronn
authors.forename: M D
authors.initials: MD
authors.lastname: Taylor
authors.forename: B L
authors.initials: BL
authors.lastname: Batley
authors.forename: S R
authors.initials: SR
authors.lastname: Rapundalo
authors.forename: M J
authors.initials: MJ
authors.lastname: Ryan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D016282:Aspartic Acid Endopeptidases; D002401:Cathepsin B; D004791:Enzyme Inhibitors; D006845:Hydrocarbons, Fluorinated; D000092502:Renin Inhibitors