MMP-3 inhibitor

Fig. 14.11 Selected examples for lead optimization under consideration of multiple parameters simultaneously (A) thrombin inhibitors, (B) p38 MAP kinase inhibitors, (C) MMP-8 inhibitors.

Matter, H., Schwab, W., Barbier, D., Billen, G., Haase, B., Neises, B., SCHUDOK, M., ThORWART, W., Brachvogel, V., Lonze, P., and Weithmann, K.U. Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field and X-Ray structure analysis. 

For these 49 MMP-8 inhibitors the systemic exposure in rabbits following oral administration... 

Fig. 9. Correlation of VolSurf descriptors with systemic exposure after oral administration in rabbits for 49 structurally diverse MMP-8 inhibitors. Left. Predicted versus experimental systemic exposure -log(AUC(orai)) from the 4 component PLS model. Right PLS loadings showing the importance of VolSurf descriptors to the prediction of the systemic exposure in rabbits.

Hudson BD, Hyde RM, Rahr E et at. (1996) Parameter based methods for compound selection from chemical databases. Quant Struct-Act Relat 15 285-289 Matter H, Schwab W, Barbier D et al. (1999) Quantitative structure-activity relationship of human neutrophil col-lagenase (MMP-8) inhibitors using comparative molecular field and X-ray structure analysis. J Med Chem 42 1908-1920... 

Among the many other non-oxicam-type substances discovered are a sultam pro-drug for potential P3-lactam thrombin inhibitors <1998BML3683>. Furthermore, an anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) pharmacophore based on the 1,2-thiazine structure has also been recently disclosed <1999BML673>. Workers at Bristol-Meyers Squibb have synthesized and evaluated sultam hydroxamates as MMP-2 inhibitors <2004JME2981>. Hydroxamate 38 displayed the best selectivity for MMP-2 over the other proteins in this superfamily of peptidases (Figure 27). As noted in Section 8.07.3.1, an X-ray crystal structure of 38 bound to the protein MMP-13 protein has been solved. 

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... 

Unfortunately, research in the area of optimization strategies is hampered by a lack of datasets on which to test new methods. Ideally the data would comprise not only what was made in the project but what could have been made—a full rank dataset of every R-group at each position with every R-group at the other positions. Recendy, one of us published a study on such a dataset (with the full rank data available as supplementary material) [40]. A series of MMP-12 inhibitors, found by a high-through-put screening, was elaborated at two positions by 50 substituents each (Figure 8.18). 

FIGURE 8.18 The series of MMP-12 inhibitors used by Pickett et al. [40] to demonstrate automated, iterative, lead optimization techniques. Reprinted with permission from Pickett et al. [40], 2011 American Chemical Society. 

Figure 4, Schematic of interactions of neutrophil enzymatic and oxidative products and endogenous protease inhibitors. Short-lived and long-lived oxidants generated by the neutrophil NADPH oxidase/myeloperoxidase system can activate latent proteases (MMP-S and MMP-9) as well as inactivate major protease inhibitors such as TIMP, armacroglobulin, and aj-protease inhibitor. Furthermore, neutrophil proteases can also interact in a synergistic fashion as evidenced by the ability of MMP-8 to degrade aj-protease inhibitor and elastase to degrade TIMP.

Matrix metalloproteinases (MMPs) are xinc-dependent proteases that favor the dissemination of metastases. MMP-1, MMP-8 and MMP-13 are coUagenases inhibitors of these enzymes could be used as anti-aging for skin. 

Arylmethyl-9-hydroxypyrazino[l,2-f]pyrimidine-l,8-dione derivatives have been claimed as anti-HIV agents <2005W02005/016927, 2005W02005/087766> 6,8-dioxo-pyrazino[l,2-f]pyrimidine-3-carboxamides 164 (Y = NH) <2004W02004/014354> and their saturated analogues <2004USP2004/034009> have been claimed as matrix metalloproteinase MMP-13 enzyme inhibitors, useful in the treatment of rheumatoid arthritis. 

The 3-carboxamido derivatives of pyrimido[6,l-c][l,4]oxazine-6,8-diones 164 (Y = 0), as with their nitrogen and sulfur-containing analogues, are matrix metalloproteinase inhibitors useful for treating MMP-13 enzyme-mediated diseases (e.g., heart failure, multiple sclerosis, and macular degeneration) <2004W02004/014354>. 

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