title: Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors.
abstract: 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.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. makoto.shiozaki@ims.jti.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Shiozaki
authors.forename: Hiroto
authors.initials: H
authors.lastname: Imai
authors.forename: Katsuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Tomoya
authors.initials: T
authors.lastname: Miura
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Yasue
authors.forename: Akira
authors.initials: A
authors.lastname: Suma
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yokota
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ogoshi
authors.forename: Julia
authors.initials: J
authors.lastname: Haas
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fryer
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Littmann
authors.forename: Steven W
authors.initials: SW
authors.lastname: Andrews
authors.forename: John A
authors.initials: JA
authors.lastname: Josey
authors.forename: Takayuki
authors.initials: T
authors.lastname: Mimura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshiuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Inaba
mesh_terms: 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
chemical_list: D003521:Cyclopropanes; D011480:Protease Inhibitors; D013449:Sulfonamides; C015766:cyclopropanecarboxylic acid; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human