title: Renin inhibitors containing esters at the P2-position. Oral activity in a derivative of methyl aminomalonate.
abstract: A series of renin inhibitors containing ester side chains at the P2 subsite are potent inhibitors of primate renin. Derivatives containing the diol isostere (ACDMH) at P1-P1' were the most potent inhibitors. Moderate selectivity for renin was observed relative to the closely related aspartic proteinase cathepsin D. The prototype compound, 4 (PD 132002), inhibited pepsin only weakly. In both high-renin normotensive and high-renin renal hypertensive monkeys, 4 produced substantial reductions in blood pressure after oral administration of 30 mg/kg. The maximum drop in blood pressure observed (24 +/- 4 mmHg) in the renal hypertensive monkey model was comparable to the drop produced by an intravenous infusion of saralasin at a maximally effective dose. Both the magnitude and duration of the oral antihypertensive effect of 4 is greater than that produced by enalkiren, CGP-38560, or CP-80794 by direct comparison in the same hypertensive monkey model. The malonate ester derivatives were prepared as ca. 65:35 mixtures of epimers. The kinetics of epimerization of 4 were investigated in detail, and it was shown to equilibrate rapidly at physiological pH (t1/2 less than 2 min). Fractional crystallization was employed to obtain the individual diastereomers in greater than 98% purity, which were indistinguishable in terms of their activity in vitro or in vivo, presumably due to rapid epimerization under the testing conditions.
authors.affiliation: Department of Chemistry, Warner-Lambert Company, Ann Arbor, Michigan 48106-1047.
authors.forename: J T
authors.initials: JT
authors.lastname: Repine
authors.forename: R J
authors.initials: RJ
authors.lastname: Himmelsbach
authors.forename: J C
authors.initials: JC
authors.lastname: Hodges
authors.forename: J S
authors.initials: JS
authors.lastname: Kaltenbronn
authors.forename: I
authors.initials: I
authors.lastname: Sircar
authors.forename: R W
authors.initials: RW
authors.lastname: Skeean
authors.forename: S T
authors.initials: ST
authors.lastname: Brennan
authors.forename: T R
authors.initials: TR
authors.lastname: Hurley
authors.forename: E
authors.initials: E
authors.lastname: Lunney
authors.forename: C C
authors.initials: CC
authors.lastname: Humblet
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D004151:Dipeptides / Q000138:chemical synthesis* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use; D004952:Esters; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D008252:Macaca fascicularis; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000627:therapeutic use; D009842:Oligopeptides / Q000627:therapeutic use; D012083:Renin / Q000097:blood; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D002402:Cathepsin D; D004151:Dipeptides; D004791:Enzyme Inhibitors; D004952:Esters; D007093:Imidazoles; D009025:Morpholines; D009842:Oligopeptides; D012083:Renin; D000092502:Renin Inhibitors; C051896:N-acetyl-1,2-dimethyl-5-hydroxylaminoimidazole; C060150:CGP 38560; C069783:PD 132002