Solid-phase synthesis of a combinatorial array of 1,3-bis(acylamino)-2-butanones, inhibitors of the cysteine proteases cathepsins K and L

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-A zido-3-amino-2,2-dimethoxybutane (4), which has the two amino groups differ entiated and the ketone protected as a a ketal, served as a surrogate for t he 1,3-diamino-2-butanone core. Amine (4) was coupled to the BAL-resin-link ed carboxylic acids derived from alpha-amino acid eaters. Evaluation of a s mall combinatorial array by measuring inhibition constants (K(i,app)s) agai nst cathepsins K, L, and B provided some structure-activity relationship tr eads with respect to selectivity and potency. Novel, potent inhibitors of c athepsins K and L were identified.