Design, Synthesis, and Biological Evaluation of Matrix Metalloproteinase Inhibitors Derived from a Modified Proline Scaffold

Abstract

The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.

A Ligand-Based Molecular Modeling Study on Some Matrix Metalloproteinase-1 Inhibitors Using Several 3D QSAR Techniques

“…8,12 The catalytic domain is the most critical one in determining both the MMP substrate and MMPI specificity. 12 The only significant structural differences within the catalytic domains of various MMPs are the conformation of surface loops. The conserved MMP core has a rms deviation of 0.3 Å when residues 113-119, 128-133, 148-152, 160-164, 181-185, 194-198, and 211-225 of MMP-1 are superimposed with residues 117-123, 132-137, 152-156, 164-168, 185-189, 198-202, and 215-229 of MMP-3.…”

“…The conserved MMP core has a rms deviation of 0.3 Å when residues 113-119, 128-133, 148-152, 160-164, 181-185, 194-198, and 211-225 of MMP-1 are superimposed with residues 117-123, 132-137, 152-156, 164-168, 185-189, 198-202, and 215-229 of MMP-3. 8 Therefore, a series of proline-based ligands built from inhibitor 14 a which is the ligand of a MMP-3 receptor 12 can be docked into the liganddepleted MMP-1 receptor. The structural features of the sulfone and diphenyl parts of the two are nearly the same, and they are superimposed well on each other (data not shown here).…”

“…Each ligand structure constructed was extracted from each structure complex using the SYBYL Extract module. 21 The total number of structures constructed was 84 which include 30 proline-(series a) 12 and 54 4-aminoproline-(series b) 14 based inhibitors. The biological activity expressed in pIC 50 for the compound set was from 5.37 to 8.52.…”

“…14 Moreover, several proline-based MMPIs designed by Cheng and colleagues also show substantial activity against MMP-1. 12 The CoMFA technique 15 has emerged as an industry standard for constructing 3D QSAR models. In using this technique, a structural alignment rule must be established beforehand to bring the orientation of a given molecule in 3D space relative to the other molecules in the analysis.…”

“…17 Meanwhile, Amin and Welsh have used CoMFA to construct some 3D QSAR models for the 39 piperazinebased MMPIs synthesized by Cheng and co-workers 12 to against MMP-3. 18 In this report, we have employed several 3D QSAR techniques on the aligned structures of 30 and 54 MMPIs of MMP-1 designed respectively by Cheng et al 12 and Natchus et al 14 for constructing some 3D QSAR models for these compounds. While both series of compounds were derived from cis-hydroxy-D-proline, the major difference in structural features between the two was that a sp 2 center for the former rather than a sp 3 one for the latter introduced at C-4 of the pyrrolidine ring.…”