Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

Autor:	Brandon Collins, W. Howard Roark, Katherine E. Palmquist, Grace E. Munie, Mark E. Schnute, Olga V. Nemirovskiy, Patrick Michael Ann Arbor La Ann Arbor O'brien, Jeffrey A. Scholten, Karl W. Aston, Jeffery N. Carroll, Lillian E. Vickery, T. Sunyer, Steven L. Settle, Joe Nahra, Hanau Cathleen E, Bruce C. Hamper, Peter G. Ruminski, Patt William Chester, Jeffrey Hitchcock, Mark Morris, Huey S. Shieh, Theresa R. Fletcher, Chiu-Fai Man, Joseph J. McDonald, Adam R. Johnson, Michael David Rogers, Arthur J. Wittwer, Alexander Pavlovsky, Richard D. Dyer, Arun Agawal
Rok vydání:	2009
Předmět:	Matrix metalloproteinase inhibitor Stereochemistry Clinical Biochemistry Pharmaceutical Science Administration Oral Tetrazoles Cartilage metabolism Matrix metalloproteinase Matrix Metalloproteinase Inhibitors Crystallography X-Ray Biochemistry chemistry.chemical_compound Catalytic Domain Drug Discovery Matrix Metalloproteinase 13 Osteoarthritis medicine Animals Tetrazole Protease Inhibitors Binding site Picolinic Acids Molecular Biology Binding Sites biology Cartilage Organic Chemistry Active site Rats Disease Models Animal Zinc medicine.anatomical_structure chemistry Enzyme inhibitor biology.protein Molecular Medicine
Zdroj:	Bioorganicmedicinal chemistry letters. 20(2)
ISSN:	1464-3405
Popis:	Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d7d21a6adaf1297782797ee424c48361 https://pubmed.ncbi.nlm.nih.gov/20005097 Zobrazit plný text záznamu Full Text from ScienceDirect