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-microM 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.
Gilbert
Adam M
AM
Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. gilbera@wyeth.com
Bursavich
Matthew G
MG
Lombardi
Sabrina
S
Georgiadis
Katy E
KE
Reifenberg
Erica
E
Flannery
Carl R
CR
Morris
Elisabeth A
EA
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects; D008956:Models, Chemical; D010003:Osteoarthritis / Q000188:drug therapy; D011348:Procollagen N-Endopeptidase / Q000378:metabolism; D051381:Rats
D000081:Acetamides; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human