Vasopeptidase Inhibitors:  Incorporation of Geminal and Spirocyclic Substituted Azepinones in Mercaptoacyl Dipeptides

Abstract

A series of 7-(di)alkyl and spirocyclic substituted azepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. Clear structure-activity relationships with respect to both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity in vitro were observed. The best in this series, compound 1g, a geminally dimethylated C-7-substituted azepinone, demonstrated excellent blood pressure lowering in animal models. Compound 1g (BMS-189921) is characterized by a good duration of activity and excellent oral efficacy in models relevant to ACE or NEP inhibition, and its activity is comparable to that of the clinically efficacious agent omapatrilat. Consequently this inhibitor has been advanced clinically for the treatment of hypertension and congestive heart failure.

METABOLISM OF [14C]GEMOPATRILAT AFTER ORAL ADMINISTRATION TO RATS, DOGS, AND HUMANS

“…The oil was chromatographed on 600 ml of silica gel eluting with 70:30 hexane/ethyl acetate. Final purification gave a TLC homogeneous compound weighing 2.93 g (57%) with a specific activity of 15.1 Ci/mg; TLC: R f ϭ 0.1 (80:20 hexane/ethyl acetate); 1 H NMR (300 MHz) and 13 C NMR (100 MHz) were consistent with the published structure (Robl et al, 1999).…”

“…1). This gave a radiolabeled carbinol that was converted to its azide and reduced catalytically with hydrogen and palladium on carbon (Robl et al, 1999). The resulting amine was cyclized in situ giving the desired caprolactam with […”

“…The azepinone was protected, and the amide linkage alkylated with ethylbromoacetate (Robl et al, 1999). After deprotection, the structural skeleton of [ 14 C]gemopatrilat was prepared by a carbodiimide-mediated coupling between the thioacetate derivative of D-phenylalanine and the radiolabeled azepinone (Singh et al, 2003).…”

“…Gemopatrilat is a potent vasopeptidase inhibitor that inhibits two key enzymes involved in the regulation of cardiovascular function: neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) (Robl et al, 1999;Hubner et al, 2001;Singh et al, 2003). ACE and NEP are zinc metalloproteases that catalyze the conversion of angiotensin I to angiotensin II (AII) and degradation of atrial natriuretic peptide (ANP), respectively (Burnett, 1999).…”

“…1). The remaining steps for the synthesis of [ 14 C]gemopatrilat were accomplished with synthetic procedures outlined in two articles (Robl et al, 1999;Singh et al, 2003). Here, we only describe the procedures used for the synthesis of the C-14-labeled precursors.…”