Design and synthesis of a series of (2R)-N-4-hydroxy-2-(3-hydroxybenzyl)-N-1-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors

A pharmacophore model of the P1' site, specific for aggrecanase, was define d using the specificity studies of the matrix metalloproteinases and the si milar biological activity of aggrecanase and MMP-8. Incorporation of the si de chain of a tyrosine residue into compound 1 as the P1' group provided mo dest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-ami no-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conform ationally constrain 2. Further optimization resulted in compound 11, a pote nt, selective, and orally bioavailable inhibitor of aggrecanase.