Matrix metalloproteinase inhibitors design

Matter, H., Schudok, M., Schwab, W., Thorwart, W., Barrier, D., Billen, G., Haase, B., Neises, B., Weithmann, K., WOLLMANN, T. Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors design, synthesis and structure-activity relationship. Bioorg. Med. Chem. 2002, 10(11), 3529-3544. 

Tetrahydroisoquinoline-3-carboxylate based matrix metalloproteinase inhibitors design, synthesis and structure-activity relationship. Bioorg. Med. Chem. 2002, 10, 3529-3544. 

The ability of hydroxamic acids to act as bidentate ligands has made this functional group a key component in the design of most matrix metalloproteinase inhibitors. Due to its labile and diprotic nature, the hydroxamate is typically installed in its protected form at the end of the synthetic sequence. ... 

S. Furumoto, R. Iwata, T. Ido, Design and synthesis of fluorine-18 labeled matrix metalloproteinase inhibitors for cancer imaging, J. Label. Compd. Radiopharm. 45 (2002) 975-986. 

Structural Implications in the Design of Matrix-Metalloproteinase Inhibitors... 

Whittaker M, Floyd CD, Brown P et al (1999) Design and therapeutic application of matrix metalloproteinase inhibitors. Chem Rev 99 2735-2776... 

Skiles JW, Gonnella NC, Jeng AY (2001) The design, structure, and therapeutic application of matrix metalloproteinase inhibitors. Curr Med Chem 8 425-474... 

Matter H, Schudok M (2004) Recent advances in the design of matrix metalloproteinase inhibitors. Curr Opin Drug Disc Dev 7 513-535... 

H. Tschesche, Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-l,3,4-thiadiazine scaffold,/. Med. Chem. 2001, 44, 3231-3243. 

Matrix metalloproteinase inhibitors that are designed to inhibit invasion of cancer cells and prevent formation of metastases. 

Spurlino, J.C. Structural implications in the design of matrix-metalloproteinase inhibitors. In Structure-Based Drug Design Veerapandian, P., Ed. Marcel Dekker, Inc. NewYork, 1997 171-189. 

Nuti, E., Tuccinardi, T. and Rossello, A. (2007) Matrix metalloproteinase inhibitors new challenges in the era of post broad-spectrum inhibitors. Current Pharmaceutical Design, 13, 2087-2100. 

B.G. Rao, Recent Developments in the Design of Specific Matrix Metalloproteinase Inhibitors Aided by Structural and Computational Studies , p. 295... 

Design and therapeutic application of matrix metalloproteinase heterocyclic inhibitors 99CRV2735. 

Fig. 3 The SAR by NMR approach. Example of a small bidentate molecule designed using this approach. The example shown is for the design of a potent inhibitors of the matrix metalloproteinase MMP3. (a) Docked structures of the identified fragment leads are shown with cyan carbons, whereas the linked compound is shown with green carbon atoms. All structures were experimentally determined by NMR. (b) Chemical structures (and in vitro potencies) of the fragment leads and subsequent high-affinity linked compounds. Adapted from [7]...

In a study conducted by Szardenings et various combinatorial libraries of DPKs scaffolds were created to design and evaluate the activity of DPKs as inhibitors of the matrix metalloproteinases, namely, collegenase-1 and gelatinase B. This study created structure-activity relationships (SAR) for side chains attached to a DPK core structure. These enzymes are therapeutic targets with indications in the treatment of cancer, arthritis, autoimmunity, and cardiovascular disease. 

The metalloproteases (MPs) and matrix metalloproteinases (MMPs) are a class of metallohydrolases of particular interest to the pharmaceutical industry due to their role in a number of pathological processes [81-83], The lack of an enzyme-bound nucleophilic residue in the metallohydrolases complicates the design of ABPP probes for this class of enzymes. Rather than mechanism-based and electrophilic probes for ABPP, photoreactive variants of reversible inhibitors of metallohydrolases have been developed [84-86]. These reversible inhibitors usually contain a hydroxamate moiety that is capable of chelating the catalytic zinc ion in a bidentate manner [79, 80]. The hydroxamate moiety was incorporated into the first generation of metallohydrolase ABPP probes along with a benzophenone group capable of covalent bond formation upon UV irradiation (Scheme 4). 

Fujisawa, T., Odake, S., Ogawa, Y., Yasuda, J., Morita, Y., and Morikawa, T. (2002) Design and synthesis of sulphur based inhibitors of matrix metalloproteinase-1. Chemical and Pharmaceutical Bulletin, 50, 239-252. 

Jacobson, I. C., Reddy, P. G., Wasserman, Z. R., et al. (1998) Structure-based design and synthesis of a series of hydroxamic acids with a quaternary-hydroxy group in PI as inhibitors of matrix metalloproteinases. Bioorganic Medicinal Chemistry Letters, 8, 837-842. 

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