Design and Synthesis of Piperazine-Based Matrix Metalloproteinase Inhibitors

Abstract

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 Zn(2+), 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.

Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases

“…In this report, we demonstrated that IM CD34 ϩ cells are more effective in transmigrating through a reconstituted basement membrane and that this aberrant migratory behavior could be inhibited by incubation with 2 MMP inhibitors, o-phenanthroline and MMP-9/MMP-13 Inhibitor I, and with interferon-␣. 14,31,32 These data suggest that the active up-regulation of MMP by IM CD34 ϩ cells is an intrinsic property of IM, which might also play a role in their preferential mobilization into the PB.…”

“…Each experiment was performed in triplicate and repeated at least twice. To examine the role of MMPs in the migration of CD34 ϩ cells through Matrigel, 2 inhibitors of MMPs, MMP-9/MMP-13 Inhibitor I (Calbiochem, La Jolla, CA) 31 and o-phenanthroline (Sigma, St Louis, MO), 14 as well as interferon-␣ (R&D Systems), which down-regulates the transcription of MMP-9, 32 were used. For these experiments, cells were preincubated overnight with 10 nmol/L MMP-9/MMP-13 Inhibitor I or 10 nmol/L o-phenanthroline, or with 100 ng/mL interferon-␣ before being loaded into the upper compartments of the Boyden chambers.…”

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

“…carboxylic acid derivatives 23 [150], 1,4-piperazines 24 [151,152], 1,3-piperazines 25 [71] (for a related series see [153]), and tetrahydro-1H- [1,4]diazapine-2-carboxylic hydroxamates 26 [154].…”

“…Inhibitors derived from d,l-piperazinecarboxylic acid have been described [151,152]. The design involves the incorporation of a hydroxamic acid as the bidentate chelating agent for the catalytic zinc, placement of a sulfonamide group at the 1N-position of the piperazine ring in order to fill the S 1´ pocket of the enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and oral absorption.…”

Analysis of the Application of MMP-9 Inhibitor in Skin Melanoma: Experimental Study

“…MMP-9 is actively expressed in melanoma-B16 cells [1,2,6,14]. Therefore, selective MMP-9 inhibitor I (C 27 H 33 N 3 O 5 S; Calbiochem) at concentration of 5 nM providing selective MMP-9 inhibition was injected intramuscularly to experimental animals for 7 days starting from day 10 after tumor transplantation [3]. Controls received no treatment.…”