Novel N-substituted 2-phenyl-1-sulfonylamino-cyclopropane carboxylates as selective ADAMTS-5 (Aggrecanase-2) inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 6; pp. 1575 - 1580
• Main Authors: SHIOZAKI, Makoto, MAEDA, Katsuya, MIMURA, Takayuki, SHINOZAKI, Yuichi, YOSHIUCHI, Hiromi, INABA, Takashi, MIURA, Tomoya, OGOSHI, Yosuke, HAAS, Julia, FRYER, Andrew M, LAIRD, Ellen R, LITTMANN, Nicole M, ANDREWS, Steven W, JOSEY, John A
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15.03.2009
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAMTS5 Protein; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carboxylic Acids - chemistry; Drug Design; Humans; Inhibitory Concentration 50; Medical sciences; Models, Chemical; Molecular Conformation; Molecular Structure; Osteoarthritis - drug therapy; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - pharmacology; Protein Structure, Tertiary; Structure-Activity Relationship; Cyclopropane derivatives; Sulfonamide; Enzyme; Metalloendopeptidases; Selectivity; ADAMTS-5 inhibitors; In vitro; Peptidases; Structure activity relation; Carboxylic acid; Biphenyl derivatives; Chlorine Organic compounds; Binding mode; Hydrolases; Inhibitor; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.02.024

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.