Matrix Metalloproteinase Inhibitors Based on the 3-Mercaptopyrrolidine Core

Abstract

New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamido pyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are capable of modulating activities of several MMPs in the low nanomolar range, including MMP-2 (~2 to 50 nM), MMP-13 (~2 to 50 nM), and MMP-14 (~4 to 60 nM). Additionally these compounds are selective to intermediate- and deep-pocket MMPs but not shallow-pocketed MMPs (e.g., MMP-1, ~850 to >50,000 nM; MMP-7, ~4,000 to >25,000 nM). Our previous work with the mercaptosulfide functionality attached to both cyclopentane and pyrrolidine frameworks demonstrated that the cis-(3S,4R)-stereochemistry was optimal for all of the MMPs tested. However, in our newest compounds an interesting shift of preference to the trans-form of the mercaptosulfonamides was observed with increased oxidative stability and biological compatibility. We also report several kinetic and biological characteristics showing that these compounds may be used to probe the mechanistic activities of MMPs in disease.

A new synthetic matrix metalloproteinase inhibitor reduces human mesenchymal stem cell adipogenesis

“…During our earlier investigations with the YHJ series of thiol MMP inhibitors, we showed that while potent, they displayed lower levels of stability than hydroxamate compounds under standard enzyme inhibition assay conditions [ 26 ]. Despite having lower stability than the hydroxamate MMPI GM6001, YHJ-7-52 reduced lipid accumulation by similar amounts ( Fig 3 ).…”

“…The mercaptosulfide matrix metalloproteinase (MMP) inhibitor, YHJ-7-52, and its structural control, YHJ-7-82, were designed and synthesized by Drs. Martin A. Schwartz and Yonghao Jin as described [ 24 , 26 ]. GM6001 was synthesized by Dr. Yonghao Jin.…”

“…However, the affinity for Zn 2+ displayed by hydroxamate ZBGs tends to overwhelm proteinase specificity and lead to target promiscuity. As a result, our group focused on developing MMPIs that contain the less implemented mercaptan ZBG [ 17 – 26 ]. The current YHJ series of MMPIs incorporates a mercaptosulfonamide attached to a diphenyl ether to increase selectivity between MMPs based on S1’ pocket depth [ 25 – 28 ].…”

“…The current YHJ series of MMPIs incorporates a mercaptosulfonamide attached to a diphenyl ether to increase selectivity between MMPs based on S1’ pocket depth [ 25 – 28 ]. Our latest inhibitors also display potencies similar to hydroxamate MMPIs for a number of MMPs [ 26 ]. Consequently, we sought to determine if one of our most promising inhibitors, YHJ-7-52, could affect the adipogenic differentiation of hMSCs.…”

Metalloproteinases promote plaque rupture and myocardial infarction: A persuasive concept waiting for clinical translation

“…Table 1 summarises the prospects for developing therapy against myocardial infarction by inhibiting individual MMPs. Such selective targeting appears feasible even with existing chemistries [82]; and innovative approaches are continually emerging [83]. The final missing link is the development of surrogate endpoints, most likely based on non-invasive imaging [59], to bridge the gap between small-scale phase II and costly phase III trials.…”