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Despite a high degree of structural similarity, it is known that MMP2 and MMP9 have distinct roles in the angiogenic switch and in cell migration, as they activate diverse signaling pathways. Indeed, inhibition of MMP2 and MMP9 can show beneficial or detrimental effects depending on the stage of tumor progression. Thus, the selective inhibition of gelatinases is of relevance for a successful drug lead, which has to be achieved despite the high structural similarity of the two gelatinases. Herein, the synthesis and evaluation of d-proline-derived hydroxamic acids containing amino appendages at C-4 as gelatinase inhibitors are reported. Inhibition assays enabled the identification of a > 200-fold selective MMP9 inhibitor when Lys was considered as a C-4 substituent, thus addressing gelatinase selectivity beyond the S1' subsite, which is a major driver for selectivity. Molecular docking studies revealed the basic moiety of Lys as detrimental for inhibition of MMP2 as compared to MMP9., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To facilitate the discovery of FAP inhibitors, a convenient cell-based fluorescent assay was developed by using a commonly available U87MG cell line and a FAP-specific substrate Suc-Gly-Pro-AMC. The assay enabled the fast determination of multiple IC 50 s by simply incubating a solution of phosphate-buffered saline in a 96-well plate within 30 min. The substrate specificity, cross-reaction and other related conditions were systematically optimized. This method was successfully applied to determine the IC 50 s of seven known inhibitors. The results are in consistence with the trend reported, which indicating that this practical assay is a valuable method to accelerate the discovery of FAP inhibitor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure-activity relationship (SAR) data for this class of compounds as inhibitors of fibroblast activation protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Four oligomeric procyanidins were isolated from the MeOH extracts of the leaves of Crataegus pinnatifida (Rosaceae). Investigation of collagenase and gelatinase inhibitory natural components afforded four oligomeric procyanidins. Of these, 2 and 3 exhibited collagenase inhibitory activity (IC(50)) at a concentration of less than 1 microM, and 3 showed gelatinases A and B inhibitory activity (IC(50)) at 0.4 and 2.3 microM, respectively., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

A number of recent researches have demonstrated the therapeutic effects of glucosamine (Glc) in a range of human diseases including arthritis. For the first time, we identified that a novel Glc derivative having quaternized amino functionality (QAGlc) suppresses MMP-9 and MMP-2, gelatinases in HT1080, human fibrosarcoma cells at 40microg/ml, following stimulation with PMA. Reporter gene assay results revealed that, the mechanism of suppression involves decreased transcriptional activation of MMP-9 and MMP-2 via transcription factors NF-kappaB and AP-1. However based on western blot results, QAGlc did not attenuate the nuclear translocation of both NF-kappaB and AP-1. Apparently, phorbol myristate acetate (PMA) stimulated expressions of ERK, JNK and p38 were altered in the presence of potent tumour inducer, phorbol myristate acetate QAGlc, suggesting their suppression also contributes to QAGlc-mediated inhibition of MMP-9 and MMP-2. Moreover, the ability of QAGlc to inhibit gelatinases was confirmed by its ability to act against invasiveness of HT1080 cells through extracellular matrix components.

SB-3CT is a thiirane-containing inhibitor of the gelatinase class of matrix metalloprotease enzymes. In support of the mechanistic study of this inhibition, the conformational analyses of SB-3CT (and of two methyl-substituted derivatives) were undertaken using X-ray crystallography and molecular dynamics simulation.

The introduction and the optimization of an alpha-amino substituent based on a series of alpha-hydroxy-beta-N-biaryl ether sulfonamide hydroxamates is described. The modification leads to a new series of MMP-2/MMP-9 inhibitors with enhanced inhibitory activities and improved ADME properties. An efficacy study on reducing the ischemia-induced brain edema in the rat transient middle cerebral artery occlusion (tMCAo) model is also demonstrated.

A new series of beta-N-biaryl ether sulfonamide hydroxamates as novel gelatinase inhibitors is described. These compounds exhibit good potency for MMP-2 and MMP-9 without inhibiting MMP-1. The structure-activity relationships (SAR) reveal the biaryl ether type P1' moiety together with methanesulfonamide is the optimal combination that provides inhibitory activity of MMP-9 in the single-digit nanomolar range.

A series of succinyl hydroxamate MMP inhibitors were prepared incorporating an aryl amino ketone moiety in place of the more typical C-terminal amino acid amides. Compounds of the C-terminal ketone series displayed potent inhibition of MMPs. Several compounds of the series were shown to be orally bioavailable.