title: Inhibitors of human renin with C-termini derived from amides and esters of alpha-mercaptoalkanoic acids.
abstract: New transition-state analogues bearing C-termini derived from alpha-mercaptoalkanoic acids, esters, and amides were prepared and evaluated as inhibitors of human renin. Addition of alpha-mercaptoalkanoate esters to a chiral Boc-amino epoxide intermediate led ultimately to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio derivatives. The corresponding sulfoxide and sulfone analogues were also investigated. Some of these derivatives, including one with a stable BocPhe replacement, were relatively potent inhibitors of human plasma renin, having IC50 values below 10 nM. When selected compounds were administered intravenously to sodium-deficient rhesus monkeys (Macaca mulatta) at 0.06-1 mg/kg, they reduced plasma renin activity by 87-94%. However, the accompanying drop in blood pressure was of short duration.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065.
authors.forename: W T
authors.initials: WT
authors.lastname: Ashton
authors.forename: C L
authors.initials: CL
authors.lastname: Cantone
authors.forename: R L
authors.initials: RL
authors.lastname: Tolman
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: R J
authors.initials: RJ
authors.lastname: Lynch
authors.forename: T W
authors.initials: TW
authors.lastname: Schorn
authors.forename: J F
authors.initials: JF
authors.lastname: Strouse
authors.forename: P K
authors.initials: PK
authors.lastname: Siegl
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D012083:Renin / Q000097:blood; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D004952:Esters; D012083:Renin; D013438:Sulfhydryl Compounds; D000092502:Renin Inhibitors