Rapid and efficient synthesis of a novel series of substituted aminobenzosuberone derivatives as potent, selective, non-peptidic neutral aminopeptidase inhibitors

Racemic 5-substituted 7-aminobenzocyclohepten-6-one were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. Unexpectedly, 5-thio substituted compounds showed enhanced inhibition potency with Ki values in the nanomolar range against the ‘one zinc’ aminopeptidases from the M1 family, while most of them were rather poor inhibitors of the ‘two zincs’ enzymes from the M17 family. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.

Some racemic aminobenzosuberone 2b–h were readily synthesized and evaluated as inhibitors of a panel of zinc-dependent aminopeptidases. Ki values in the nanomolar range were obtained selectively against the one zinc aminopetidase APN/CD13. The phenylthioether derivative 2d,d′ is among the most potent newly synthesized APN inhibitor and may exhibit a new type of binding mode.Figure optionsDownload as PowerPoint slide