Development of New Hydroxamate Matrix Metalloproteinase Inhibitors Derived from Functionalized 4-Aminoprolines

Abstract

A series of hydroxamates was prepared from an aminoproline scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors, such as compound 47, display broad-spectrum activity with sub-nanomolar potency for some enzymes. Modifications of the P1' portion of the molecule played a key role in affecting both potency and selectivity within the MMP family. Longer-chain aliphatic substituents in this region of the molecule tended to increase potency for MMP-3 and decrease potency for MMP-1, as exemplified by compounds 48-50, while aromatic substituents, as in compound 52, generated broad-spectrum inhibition. The data is rationalized based upon X-ray crystal data which is also presented. While the in vitro peroral absorption seemed to be less predictable, it tended to decrease with longer and more hydrophilic substituents. Finally, a rat model of osteoarthritis was used to evaluate the efficacy of these compounds, and a direct link was established between their pharmacokinetics and their in vivo efficacy.

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

“…8,12,14 The former and latter substitutions are designed for exploring the binding with the S1′ and S2′ pockets of the MMP-1 receptor, respectively. An analysis by Ligplot 4.22 program 24 on the structure of inhibitor 14 a -MMP-1 complex is presented in Figure 1.…”

“…[12][13][14] It has been suggested that these substituents could not directly affect the overall binding but would alter the conformation of proline ring to a more efficiently bound orientation. 12 This feature is also identified by the Hypo1 hypothesis on inhibitor 01 c in which a blue sphere is mapped onto the methylamine group of the inhibitor (Figure 3b).…”

“…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.…”

“…2 Therefore, based on an aminopyrrolidine scaffold, Natchus and colleagues have designed a series of MMP-1 inhibitors and found that some of these inhibitors are able to protect the degradation of cartilage in a rat model of osteoarthritis. 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.…”

“…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.…”