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

• Published in: Current medicinal chemistry Vol. 8; no. 4; pp. 425 - 474
• Main Authors: SKILES, Jerry W, GONNELLA, Nina C, JENG, Arco Y
• Format: Journal Article
• Language: English
• Published: Schiphol Bentham Science Publishers Ltd 01.03.2001; Bentham Science
• Subjects: Amino Acid Sequence; Antineoplastic agents; Autoimmune diseases; Biochemistry; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Design; General aspects; Inhibitors; Matrix metalloproteinase; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases - chemistry; Matrix Metalloproteinases - metabolism; Medical sciences; Molecular biology; Molecular Sequence Data; Molecular Structure; Osteoarthritis; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - therapeutic use; Protein Conformation; Rheumatoid arthritis; TIMP protein; Sulfone; Pathogenesis; Cardiovascular disease; Metalloendopeptidases; Review; Carcinogenesis; Phosphorus Organic compounds; Macrocycle; Vascular disease; Angiogenesis; Three dimensional structure; Domain structure; Atherosclerosis; Binding mode; Clinical trial; Mechanism of action; Ulceration; Thiol; Sulfonamide; Enzyme; Peptidomimetic compound; Hydroxamic acid; Enzyme inhibitor; Inhibitor enzyme complex; Ketone; Peptidases; Synthetic product; Hydrolases; Skin; Molecular domain; Emphysema
• ISSN: 0929-8673; 1875-533X
• DOI: 10.2174/0929867013373417

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.