Design and synthesis of carboxylate inhibitors for matrix metalloproteinases

Abstract

A series of carboxylate compounds were prepared from Nα-substituted 2,3-diaminopropionic acid and were tested for efficacy as matrix metalloproteinase (MMP) inhibitors. During modeling of the initial compound 10a, we utilized three-dimensional structure modeling software (InsightII/Discover Ver. 2.98). Some of the prepared carboxylate derivatives, such as carbamate compounds (12c, d, 22) and sulfonamide compounds (14b, c), proved to be effective MMP-1 inhibitors (with IC50 values of a 10-6M order), depending on the substituent at the Nα-position of 2,3-diaminopropionic acid. Some of them were also evaluated for inhibition of stromelysin-1 (MMP-3), and the sulfonamide compound 14c exceeded the lead compound 5b in its MMP-3 inhibitory potency. For the carbamate compounds, we investigated the minimum molecular size at which the MMP-1 inhibitory potency was maintained, and found that this was P3-P1′ compound 10b.