Matrix metalloproteinase inhibitors binding

Fig. 14.12 VolSurf model to correlate 49 matrix metalloproteinase inhibitors with different zinc-binding functionalities to rabbit oral bioavailability for metabolically stable compounds. (A) Semiquantitative PLS model 0.424, r 0.646, 4 PLS components) to rank novel synthesis candidates. Main factors influencing absorption, that is, lower polarity, capacity factors and increased hydrophobicity, are in agreement with global models for human intestinal absorption. (B) Distribution of polar and hydrophobic surfaces for two molecules with low (0981) and higher (2290) rabbit AUC from oral pharmacokinetic studies.

Other reported zinc binding chelators used in matrix metalloproteinase inhibitors are summarized in Fig. 15.26. For instance, one of the oxygens in the phosphonamide (57) binds strongly to the zinc ion, whereas the other one coordinates weakly with the metal (110). More recently, suicide substrate MMP inhibitors have appeared (58)(Fig. 15.26) (111). The se-... 

Matrix Metalloproteinase Inhibitor Metalloproteinase Structure activity relationship Radio Frequency Zinc binding group... 

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

Matrix metalloproteinase structural studies of the P -side inhibitors to date show a common set of inhibitor-enzyme interactions. This can be attributed primarily to the strong directional zinc-binding forces. Further stabilizing forces from the backbone hydrogen-bonding patterns common to a (3 sheet allow for minor adjustments due to the zinc interactions to be made while maintaining a common pharmacophore. 

In search for potent and systemically available inhibitors of the matrix metalloproteinase MMP-8 (Matter et al. 1999 Matter et al. 2002) following oral administration, a local ADME model was derived to support lead optimization. For an internal series of inhibitors on the tetrahydroisoquinoline scaffold, hydroxamic acids for zinc ion binding in 3-position are essential for MMP affinity in first generation inhibitors. However, those compounds are characterized by insufficient pharmacokinetic properties and low systemic exposure following oral administration. Driven by X-ray and 3D-QSAR studies (CoMFA), alternative Zn2+ binding groups like carboxylates were... 

Parker, M.H., Lunney, E.A., Ortwine, D.F., Pavlowsky, A.G., Humblet, C. et al. (1999) Analysis of the binding of hydroxamic acid and carboxylic acid inhibitors to the stromlysin-1 (matrix metalloproteinase-3) catalytic domain by isothermal titration calorimetry. Biochemistry 38 13592-13601. 

Sato T, Koike L, Miyata Y, Hirata M, Mimaki Y, Sashida Y, Yano M, Ito A. Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metaUoproteinases-1 production and suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells. Cancer Res 2002 62 1025-1029. 

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