Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors.
A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC50=7.4 nM, the most potent ADAMTS-5 inhibitor reported so far.
Shiozaki
Makoto
M
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. makoto.shiozaki@ims.jti.co.jp
Imai
Hiroto
H
Maeda
Katsuya
K
Miura
Tomoya
T
Yasue
Katsutaka
K
Suma
Akira
A
Yokota
Masahiro
M
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* / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D003521:Cyclopropanes; D011480:Protease Inhibitors; D013449:Sulfonamides; C015766:cyclopropanecarboxylic acid; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human