204141-22-0Relevant articles and documents
Design and synthesis of piperazine-based matrix metalloproteinase inhibitors
Cheng, Menyan,De, Biswanath,Pikul, Stanislaw,Almstead, Neil G.,Natchus, Michael G.,Anastasio, Melanie V.,McPhail, Sara J.,Snider, Catherine E.,Taiwo, Yetunde O.,Chen, Longyin,Dunaway, C. Michelle,Gu, Fei,Dowty, Martin E.,Mieling, Glen E.,Janusz, Michael J.,Wang-Weigand, Sherry
, p. 369 - 380 (2007/10/03)
A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived from dl-piperazinecarboxylic acid has been described. The design involves: incorporation of hydroxamic acid as the bidentate chelating agent for catalytic Zn2+, placement of a sulfonamide group at the 1N-position of the piperazine ring to fill the S1' pocket of the enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and peroral absorption. A unique combination of all three elements produced inhibitor 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 cocrystallized with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors.
