Novel N-substituted 2-phenyl-1-sulfonylamino-cyclopropane carboxylates as selective ADAMTS-5 (Aggrecanase-2) inhibitors.
A series of N-substituted sulfonylamino-alkanecarboxylate ADAMTS-5 (Aggrecanase-2) inhibitors has been synthesized and the in vitro enzyme SAR is discussed. This report is the first example of carboxylate-based ADAMTS-5 inhibitors which show strong potency of IC(50)<0.1muM with excellent selectivity over MMP-1 and TACE.
Shiozaki
Makoto
M
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Maeda
Katsuya
K
Miura
Tomoya
T
Ogoshi
Yosuke
Y
Haas
Julia
J
Fryer
Andrew M
AM
Laird
Ellen R
ER
Littmann
Nicole M
NM
Andrews
Steven W
SW
Josey
John A
JA
Mimura
Takayuki
T
Shinozaki
Yuichi
Y
Yoshiuchi
Hiromi
H
Inaba
Takashi
T
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071116:ADAMTS5 Protein; D002264:Carboxylic Acids / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D010003:Osteoarthritis / Q000188:drug therapy; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D011480:Protease Inhibitors; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human