Design and synthesis of carboxylate inhibitors for matrix metalloproteinases

A series of carboxylate compounds were prepared from N-alpha-substituted 2, 3-diaminopropionic acid and were tested for efficacy as matrix metalloprote inase (MMP) inhibitors. During modeling of the initial compound 10a, we uti lized three-dimensional structure modeling software (InsightII/Discover Ver . 2.98). Some of the prepared carboxylate derivatives, such as carbamate co mpounds (12c, d, 22) and sulfonamide compounds (14b, c), proved to be effec tive MMP-1 inhibitors (with ICS, values of a 10(-6) M order), depending on the substituent at the N-alpha-position of 2,3-diaminopropionic acid. Some of them were also evaluated for inhibition of stromelysin-1 (MMP-3), and th e sulfonamide compound 14c exceeded the lead compound 5b in its MMP-3 inhib itory potency. For the carbamate compounds, we investigated the minimum mol ecular size at which the MMP-1 inhibitory potency was maintained, and found that this was P-3-P-1' compound 10b.