Design and synthesis of piperazine-based matrix metalloproteinase inhibitors

A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derive d from dl-piperazinecarboxylic acid has been described. The design involves : incorporation of hydroxamic acid as the bidentate chelating agent for cat alytic Zn2+, placement of a sulfonamide group at the 1N-position of the pip erazine ring to fill the S1' pocket of the enzyme, and finally attachment o f diverse functional groups at the 4N-position to optimize potency and pero ral absorption. A unique combination of all three elements produced inhibit or 20 with high affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray crystallography data obtained for MMP-3 cocrystallize d with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors.