Abstract
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.
MeSH terms
-
ADAM Proteins / antagonists & inhibitors*
-
ADAM Proteins / chemistry*
-
ADAM Proteins / metabolism
-
ADAMTS4 Protein
-
ADAMTS5 Protein
-
Acetamides / chemical synthesis*
-
Acetamides / pharmacology*
-
Animals
-
Chemistry, Pharmaceutical / methods
-
Cytochrome P-450 CYP3A
-
Cytochrome P-450 CYP3A Inhibitors
-
Cytochrome P-450 Enzyme Inhibitors
-
Drug Design
-
Humans
-
Inhibitory Concentration 50
-
Microsomes, Liver / drug effects
-
Models, Chemical
-
Osteoarthritis / drug therapy
-
Procollagen N-Endopeptidase / metabolism
-
Rats
Substances
-
Acetamides
-
Cytochrome P-450 CYP3A Inhibitors
-
Cytochrome P-450 Enzyme Inhibitors
-
Cyp3a2 protein, rat
-
Cytochrome P-450 CYP3A
-
CYP3A4 protein, human
-
ADAM Proteins
-
ADAMTS5 Protein
-
ADAMTS5 protein, human
-
Procollagen N-Endopeptidase
-
ADAMTS4 Protein
-
ADAMTS4 protein, human