Dual Metalloprotease Inhibitors. 6. Incorporation of Bicyclic and Substituted Monocyclic Azepinones as Dipeptide Surrogates in Angiotensin-Converting Enzyme/Neutral Endopeptidase Inhibitors

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.

Highly Diastereo‐ and Enantioselective Cu‐Catalyzed Borylative Coupling of 1,3‐Dienes and Aldimines

“…[3] Copper catalysis is an efficient approach to promote the enantioselective addition of terminal allyl transmetalation reagents (e.g., with B, Si, and Sn) to imines, [4] however,C ucatalyzed asymmetric, nucleophilic addition to imines with functionalized (e.g., g-substituted) allyl metal reagents remain challenging.T his is probably due to inefficiencyo f the transmetalation event arising from increased steric hindrance,t he weak electrophilicity/reactivity of imines, and/or difficulties in predicting the regio-and stereochemical outcome of additions.N ew and efficient approaches to generating and utilizing functionalized allyl metal reagents in the presence of acopper catalyst hold promise for accessing complex homoallylic amines,a nd these methods will expand the application of catalytic asymmetric allylation chemistry.…”

Novel broad-spectrum inhibitors of bacterial methionine aminopeptidase

“…This hit contained an azepinone amide backbone and resynthesis of the compound confirmed inhibition of enzyme activity. Monocyclic and bicyclic azepinones have been incorporated as dipeptide mimics in mercaptoacyldipeptides inhibitors of angiotensin converting enzyme (ACE) [18][19][20] including the marketed ACE inhibitor benazepril. 21,22 Medicinal chemistry effort was subsequently deployed to achieve potency and physical property optimization.…”

Enzyme Inhibition and Inactivation

“…[107] The lead compound devised at BMS (5.53), which had a structure composed of part of captopril and enalapril, was found to have IC 50 values for ACE and NEP of 30 and 400 nM, respectively, which is excellent for a lead compound. [108] The thiol group was retained because subsequent to the launch of captopril it was found that the loss of taste and rash side effects initially observed were related to high dosing, not to the sulfur atom hypothesized at Merck; at a lower dose, captopril was just as effective, but without those side effects. Homologation gave a compound that was potent in vitro for both enzymes, but not very potent in vivo (5.54).…”