Novel thiol-based TACE inhibitors: rational design, synthesis, and SAR of thiol-containing aryl sulfonamides.
A series of potent thiol-containing aryl sulfonamide TACE inhibitors was designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 4b has shown excellent in vitro potency against the isolated TACE enzyme and good selectivity over MMP-2, -7, -8, -9, and -13. The X-ray structure of 4b bound to TACE was obtained.
Govinda Rao
B
B
Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA. govinda_rao@vrtx.com
Bandarage
Upul K
UK
Wang
Tiansheng
T
Come
Jon H
JH
Perola
Emanuele
E
Wei
Yunyi
Y
Tian
Shi-Kai
SK
Saunders
Jeffrey O
JO
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D003424:Crohn Disease / Q000188:drug therapy; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D045726:Metalloproteases; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D013449:Sulfonamides; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human