Potent and selective aggrecanase inhibitors containing cyclic P1 substituents

Autor:	James M. Trzaskos, Rui-Qin Liu, Elizabeth C. Arner, David D. Christ, Carl P. Decicco, Wenqing Yao, Robert J. Cherney, Maryanne B. Covington, Mingxin Qian, Robert C. Newton, Ron L Magolda, Dayton T. Meyer, Zelda R. Wasserman, Ruowei Mo, Micky D. Tortorella, Li Wang
Rok vydání:	2003
Předmět:	medicine.drug_class Stereochemistry Clinical Biochemistry Azetidine Pharmaceutical Science Carboxamide Hydroxamic Acids Biochemistry Chemical synthesis chemistry.chemical_compound Dogs Endopeptidases Drug Discovery medicine Animals Protease Inhibitors Molecular Biology Aggrecanase chemistry.chemical_classification Hydroxamic acid biology Organic Chemistry Rats Isoenzymes Enzyme chemistry Enzyme inhibitor biology.protein Molecular Medicine Cattle Indicators and Reagents Piperidine Half-Life
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 13:1297-1300
ISSN:	0960-894X
Popis:	Anti-succinate hydroxamates with cyclic P1 motifs were synthesized as aggrecanase inhibitors. The N-methanesulfonyl piperidine 23 and the N-trifluoroacetyl azetidine 26 were the most potent aggrecanase inhibitors both having an IC50=3 nM while maintaining >100-fold selectivity over MMP-1, -2, and -9. The cyclic moieties were also capable of altering in vivo metabolism, hence delivering low clearance compounds in both rat and dog studies as shown for compound 14.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::297fbc397746e76e53e9b9952620e792 https://doi.org/10.1016/s0960-894x(03)00124-0 Zobrazit plný text záznamu Full Text from ScienceDirect