title: 1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives.
abstract: A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.
authors.affiliation: Department of Chemistry, ICI Pharmaceuticals, Mereside, Cheshire, U.K.
authors.forename: D A
authors.initials: DA
authors.lastname: Roberts
authors.forename: R H
authors.initials: RH
authors.lastname: Bradbury
authors.forename: D
authors.initials: D
authors.lastname: Brown
authors.forename: A
authors.initials: A
authors.lastname: Faull
authors.forename: D
authors.initials: D
authors.lastname: Griffiths
authors.forename: J S
authors.initials: JS
authors.lastname: Major
authors.forename: A A
authors.initials: AA
authors.lastname: Oldham
authors.forename: R J
authors.initials: RJ
authors.lastname: Pearce
authors.forename: A H
authors.initials: AH
authors.lastname: Ratcliffe
authors.forename: J
authors.initials: J
authors.lastname: Revill
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002143:Callitrichinae; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D007275:Injections, Intravenous; D008969:Molecular Sequence Data; D011719:Pyrazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000092502:Renin Inhibitors
chemical_list: D011719:Pyrazines; D014230:Triazoles; D000092502:Renin Inhibitors