Design, Synthesis And Calpain Inhibitory Activity Of α-Ketoamides

Calpains are a family of intracellular calcium-dependent cysteine proteases,which are ubiquitously expressed in many cells and tissues.The calpains are implicated in numerous calcium-regulated cellular processes,such as signal transduction,cell proliferation, differentiation and apoptosis.Accumulated evidence of the involvement ofμ-calpain in human diseases has attracted much interest in the identification of calpain inhibitors and in the elucidation of pathological or physiological roles and their therapeutic potentials.In connection with the previously reported SARs of calpain inhibitors and our on-going work to identify the new scaffold forμ-calpain inhibitors,we designed 4-aryl-4-oxobutanoic acid amides and quinolinone carboxamides as alternative scaffold forμ-calpain inhibitors to investigate the requirement for a hydrogen bound donor of acceptor group for efficient inhibitor's binding.Furthermore,7 different kinds of arylalkyl substituents were introduced to the terminus part to find the interaction change with enzyme.The in vitroμ-calpain inhibitory activities of the prepared two series of compounds were evaluated using humanμ-calpain isolated from erythrocytes.Suc-Leu-Tyr-AMC was used as the fluorogenic substrate.MDL-28,170 and KYS-4516 was used as positive control. Among them,10 compounds(1b-2,1c-2,1f-2,1g-2,1j-2,1k-2,1l-2,1n-2,1j-4 and 1n-4) showed good potency ofμ-calpain inhibitory activities with IC₅₀ value less than 1μM.The preliminary SARs of these compounds were discussed,which would provide useful information for the further study.