title: 1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives.
abstract: A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.
authors.affiliation: Department of Chemistry, ICI Pharmaceuticals, Mereside, Cheshire, U.K.
authors.forename: R H
authors.initials: RH
authors.lastname: Bradbury
authors.forename: J S
authors.initials: JS
authors.lastname: Major
authors.forename: A A
authors.initials: AA
authors.lastname: Oldham
authors.forename: J E
authors.initials: JE
authors.lastname: Rivett
authors.forename: D A
authors.initials: DA
authors.lastname: Roberts
authors.forename: A M
authors.initials: AM
authors.lastname: Slater
authors.forename: D
authors.initials: D
authors.lastname: Timms
authors.forename: D
authors.initials: D
authors.lastname: Waterson
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002143:Callitrichinae; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D008958:Models, Molecular; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D000092502:Renin Inhibitors
chemical_list: D000596:Amino Acids; D011719:Pyrazines; D014230:Triazoles; D000092502:Renin Inhibitors