title: Renin inhibitors. III. Synthesis and structure-activity relationships of transition-state inhibitors containing dihydroxyethylene isostere at the P1-P1 site.
abstract: The design, synthesis and structure-activity relationships of transition-state inhibitors containing the dihydroxyethylene isostere at the scissile site are described. The compounds with (2S,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol at the P1-P1 site are potent renin inhibitors. (2S,3R,4S)-4-[N-[(2S)-3-Ethylsulfonyl-2-(1-naphthylmethyl)propiony l]-L- norleucyl]amino-5-cyclohexyl-1-morpholino-2,3-pentanediol (2) (BW-175), which is the most potent inhibitor (IC50: 3.3 nM against human renin) in this series, poorly inhibits cathepsin D (IC50: 26000 nM) and pepsin (IC50: > 100000 nM), and thus it is specific for renin. Compound 2 contains only one amino acid and showed an oral bioavailability of 2.8% at 10 mg/kg and 9.7% at 30 mg/kg in rats. The interaction between renin and inhibitor 2 is discussed on the basis of molecular modeling studies.
authors.affiliation: Structural Biology & Chemistry, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Atsuumi
authors.forename: H
authors.initials: H
authors.lastname: Funabashi
authors.forename: M
authors.initials: M
authors.lastname: Nakano
authors.forename: Y
authors.initials: Y
authors.lastname: Koike
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: J
authors.initials: J
authors.lastname: Harada
authors.forename: K
authors.initials: K
authors.lastname: Matsuyama
authors.forename: T
authors.initials: T
authors.lastname: Ikenaga
authors.forename: H
authors.initials: H
authors.lastname: Morishima
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002144:Callithrix; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology*; D009646:Norleucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000092502:Renin Inhibitors
chemical_list: D000959:Antihypertensive Agents; D009025:Morpholines; D009646:Norleucine; D000092502:Renin Inhibitors; C059042:BW 175