Potent and selective aggrecanase inhibitors containing cyclic P1 substituents

Abstract Anti-succinate hydroxamates with cyclic P1 motifs were synthesized as aggrecanase inhibitors. The N -methanesulfonyl piperidine 23 and the N -trifluoroacetyl azetidine 26 were the most potent aggrecanase inhibitors both having an IC 50 =3 nM while maintaining >100-fold selectivity over MMP-1, -2, and -9. The cyclic moieties were also capable of altering in vivo metabolism, hence delivering low clearance compounds in both rat and dog studies as shown for compound 14 .