title: Renin inhibitors. II. Synthesis and structure-activity relationships of N-terminus modified inhibitors containing a homostatine analogue.
abstract: The synthesis and structure-activity relationships of N-terminus modified renin inhibitors containing the homostatin analogue, (2RS,4S,5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid, are described. The compounds having a 3-alkyl (or aryl)sulfonylpropionyl residue at the N-terminus are found to be potent inhibitors which contain two amino acids. (2RS,4S,5S)-N-Isobutyl-5-[N-[(2S)-3-ethylsulfonyl-2-(1- naphthylmethyl)propionyl]-L-norleucyl]-amino-2-ethyl-4-hydroxy-7- methyloctanamide (20) has an IC50 of 0.5 nM against human plasma renin and the oral bioavailability of 20 is 0.73% in rats. Interaction between renin and the N-terminus of 1 and 20 is discussed in molecular modeling studies.
authors.affiliation: Chemistry of Natural Products, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Atsuumi
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: H
authors.initials: H
authors.lastname: Funabashi
authors.forename: K
authors.initials: K
authors.lastname: Matsuyama
authors.forename: M
authors.initials: M
authors.lastname: Nakano
authors.forename: Y
authors.initials: Y
authors.lastname: Sawasaki
authors.forename: K
authors.initials: K
authors.lastname: Funabashi
authors.forename: H
authors.initials: H
authors.lastname: Morishima
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D008956:Models, Chemical; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000596:Amino Acids; D009842:Oligopeptides; D000092502:Renin Inhibitors