title: Novel thiol-based TACE inhibitors: rational design, synthesis, and SAR of thiol-containing aryl sulfonamides.
abstract: 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.
authors.affiliation: Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA. govinda_rao@vrtx.com
authors.forename: B
authors.initials: B
authors.lastname: Govinda Rao
authors.forename: Upul K
authors.initials: UK
authors.lastname: Bandarage
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.forename: Jon H
authors.initials: JH
authors.lastname: Come
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.forename: Yunyi
authors.initials: Y
authors.lastname: Wei
authors.forename: Shi-Kai
authors.initials: SK
authors.lastname: Tian
authors.forename: Jeffrey O
authors.initials: JO
authors.lastname: Saunders
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D013449:Sulfonamides; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human