Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors.
Aggrecanases are recently discovered enzymes that cleave aggrecan, a key component of cartilage. Aggrecanase inhibitors may provide a unique means to halt the progression of cartilage destruction in osteoarthritis. The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 microg/mL and has an oral bioavailability in rat of 35%.
Xiang
Jason S
JS
Department of Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
Hu
Yonghan
Y
Rush
Thomas S
TS
Thomason
Jennifer R
JR
Ipek
Manus
M
Sum
Phaik-Eng
PE
Abrous
Leila
L
Sabatini
Joshua J
JJ
Georgiadis
Katy
K
Reifenberg
Erica
E
Majumdar
Manas
M
Morris
Elisabeth A
EA
Tam
Steve
S
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071121:ADAMTS4 Protein; D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017364:Collagenases / Q000378:metabolism; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors*; D011509:Proteoglycans / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
D001713:Biphenyl Compounds; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011509:Proteoglycans; D013449:Sulfonamides; D051722:ADAM Proteins; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein