title: Renin inhibitors containing a pyridyl amino diol derived C-terminus.
abstract: Based on the concept of transition-state analogs, a series of nonpeptide renin inhibitors with the new (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane moiety at the C-terminal functionality were synthesized and evaluated for inhibition of renin both in vitro and in vivo. All compounds exhibited potencies in the nanomolar or even subnanomolar range when tested versus human renin in vitro. Selected inhibitors were evaluated in anesthetized, sodium-depleted rhesus monkeys and produced a marked reduction in mean arterial blood pressure (MAP) upon intraduodenal administration of a dose of 2 mg/kg. Compound 38 (S 2864) containing an amino piperidyl succinic acid derived N-terminal is the most promising member in this series. 38 inhibited human renin with an IC50 of 0.38 nM, did not affect other human aspartic proteinases, and decreased mean arterial blood pressure significantly by 27% with a duration of action of 90 min after administration of 2 mg/kg id in anesthetized, sodium-depleted rhesus monkeys.
authors.affiliation: Hoechst AG, Frankfurt/M., Germany.
authors.forename: H
authors.initials: H
authors.lastname: Heitsch
authors.forename: R
authors.initials: R
authors.lastname: Henning
authors.forename: H W
authors.initials: HW
authors.lastname: Kleemann
authors.forename: W
authors.initials: W
authors.lastname: Linz
authors.forename: W U
authors.initials: WU
authors.lastname: Nickel
authors.forename: D
authors.initials: D
authors.lastname: Ruppert
authors.forename: H
authors.initials: H
authors.lastname: Urbach
authors.forename: A
authors.initials: A
authors.lastname: Wagner
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012756:Sheep; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000596:Amino Acids; D009842:Oligopeptides; D011725:Pyridines; D000092502:Renin Inhibitors; C083397:S 2864