N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2)

N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared. Selected compounds 10, 14, 25, and 53 show sub-μM ADAMTS-5 potency and good selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP-13,...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-12, Vol.18 (24), p.6454-6457
Hauptverfasser:	Gilbert, Adam M., Bursavich, Matthew G., Lombardi, Sabrina, Georgiadis, Katy E., Reifenberg, Erica, Flannery, Carl R., Morris, Elisabeth A.
Format:	Artikel
Sprache:	eng
Schlagworte:	Acetamides - chemical synthesis Acetamides - pharmacology ADAM Proteins - antagonists & inhibitors ADAM Proteins - chemistry ADAM Proteins - metabolism ADAMTS-4 ADAMTS-5 ADAMTS4 Protein ADAMTS5 Protein Aggrecanase-1 Aggrecanase-2 Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Chemistry, Pharmaceutical - methods Cytochrome P-450 CYP3A Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 Enzyme Inhibitors Drug Design Humans Inhibitory Concentration 50 Medical sciences Metalloproteases Microsomes, Liver - drug effects Models, Chemical Osteoarthritis Osteoarthritis - drug therapy Pharmacology. Drug treatments Procollagen N-Endopeptidase - metabolism Rats
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Beschreibung
Zusammenfassung:	N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared. Selected compounds 10, 14, 25, and 53 show sub-μM ADAMTS-5 potency and good selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP-13, and MMP-12. Compound 53 shows a good balance of potent ADAMTS-5 inhibition, moderate CYP3A4 inhibition and good rat liver microsome stability. This series of compounds represents progress towards selective ADAMTS-5 inhibitors as disease modifying osteoarthritis agents.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2008.10.065