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

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

“…9 phosphonic and phosphinic acid [92]. However, since they rely in zinc chelating for activity, a poor selectivity towards MMPs have been observed [93] and disappointing results have been obtained for most compounds except phosphinic acids (reviewed by [11]).…”

Valine-based biphenylsulphonamide matrix metalloproteinase inhibitors as tumor imaging agents

“…Other zinc-binding ligands that have been utilized include reverse hydroxamic acids, carboxylic acids, thiols, and thiadiazoles (Skiles et al, 2001). Tryptophane-based biphenylsulphonamide matrix metalloproteinase inhibitors were synthesized, evaluated in vitro; in vivo and as imaging agent and were published previously (Oltenfreiter et al, 2004(Oltenfreiter et al, , 2005a.…”

“…Structural changes made to the biphenyl ring system, the α-position to carboxylic acid and the carboxylate moiety, have an influence on biological activity (O'Brien et al, 2000). Earlier experiments and SAR studies showed that biphenylsulfonamides substituted with bromine in the 4'-position significantly improved the in vitro activity and exhibited superior pharmacokinetics (C max , t 1/2 , AUCs) relative to the compounds without bromine (Skiles et al, 2001). Halogens appended to the 4'-position of the * Supported by EU Grant LSHC- CT-2003-503297 'cancerdegradome'. biphenyl ring, in general, increased potency against some MMPs.…”

“…The origin of these musculoskeletal side effects is at present undetermined, although several hypotheses have been put forth. Both the inhibition of MMP-1 and the inhibition of tumor necrosis factor (TNF) receptor shedding have been proposed as mechanisms for the origin of this troublesome complication (Skiles et al, 2001). Taking these reflections into account the Valine analogues of the earlier published Tryptophane-based biphenylsulphonamide matrix metalloproteinase inhibitors have been synthesized and evaluated.…”

Target-Activated Prodrugs (TAPs) for the Autoregulated Inhibition of MMP12

“…For this reason, it was speculated that an improvement in the selectivity toward a specific MMP and a better understanding of the disease would produce useful treatments in the future. 8 As a result, a large number of low nanomolar MMP inhibitors with improved selectivity were synthesized, but their applicability in the clinic has not yet been proven. 9 Therefore, there is still a need for new strategies to develop MMP inhibitors that avoid side effects and make MMPs druggable targets.…”