Dual metalloprotease inhibitors. 6. Incorporation of bicyclic and substituted monocyclic azepinones as dipeptide surrogates in angiotensin-converting enzyme/neutral endopeptidase inhibitors

J A Robl; M P Cimarusti; L M Simpkins; B Brown; D E Ryono; J E Bird; M M Asaad; T R Schaeffer; N C Trippodo

doi:10.1021/jm950677a

Dual metalloprotease inhibitors. 6. Incorporation of bicyclic and substituted monocyclic azepinones as dipeptide surrogates in angiotensin-converting enzyme/neutral endopeptidase inhibitors

J Med Chem. 1996 Jan 19;39(2):494-502. doi: 10.1021/jm950677a.

Authors

J A Robl¹, M P Cimarusti, L M Simpkins, B Brown, D E Ryono, J E Bird, M M Asaad, T R Schaeffer, N C Trippodo

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

PMID: 8558518
DOI: 10.1021/jm950677a

Abstract

A series of substituted monocyclic and bicyclic azepinones were incorporated as dipeptide surrogates in mercaptoacetyl dipeptides with the desire to generate a single compound which would potently inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). Many of these compounds displayed excellent potency against both enzymes. Two of the most potent compounds, monocyclic azepinone 2n and bicyclic azepinone 3q, demonstrated a high level of activity versus ACE and NEP both in vitro and in vivo.

MeSH terms

Amino Acid Sequence
Angiotensin-Converting Enzyme Inhibitors / pharmacology*
Animals
Antihypertensive Agents / pharmacology
Azepines / pharmacology*
Dipeptides / pharmacology*
Kidney / enzymology
Lung / enzymology
Male
Metalloendopeptidases / antagonists & inhibitors*
Molecular Sequence Data
Neprilysin / antagonists & inhibitors*
Protease Inhibitors / pharmacology*
Rats
Rats, Sprague-Dawley

Substances

Angiotensin-Converting Enzyme Inhibitors
Antihypertensive Agents
Azepines
Dipeptides
Protease Inhibitors
Metalloendopeptidases
Neprilysin