Design and Synthesis of Carboxylate Inhibitors for Matrix Metalloproteinases

概要

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A series of carboxylate compounds were prepared from N^α-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 IC_<50> values of a 10^<-6>M order), depending on the substituent at the N^α-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 P_3-P'_1 compound 10b.
公益社団法人日本薬学会の論文
2001-10-01