Solid-Phase Synthesis of a Combinatorial Array of 1,3-Bis(acylamino)-2-butanones, Inhibitors of the Cysteine Proteases Cathepsins K and L

摘要

To More rapidly prepare members of the 1,3-bis(acylamino)-2-butanone class of cysteine protease inhibitors, a solid-phase synthesis was developed. 1-Azido-3-amino-2, 2-dimethoxybutane (4), which has the two amino groups differentiated and the ketone protected as a a ketal, served as a surrogate for the 1,3-diamino-2-butanone core. Amine (4) was coupled to the BAL-resin-linked carboxylic acids derived from #alpha#-amino acid esters. Evaluation of a small combinatorial array by measuring inhibition constants (K_(i,app)s) against cathepsins K, L, and B provided some structure--activity relationship trends with respect to selectivity and potency. Novel, potent inhibitors of cathepsins K and L were identified.