Novel thiol-based TACE inhibitors. Part 2: Rational design, synthesis, and SAR of thiol-containing aryl sulfones.
A series of potent thiol-containing aryl sulfone TACE inhibitors were designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 8b showed excellent in vitro potency against the isolated enzyme and good selectivity over MMP-2, -7, -8, -9, and -13. The X-ray structure of 8b in complex with TACE was also obtained.
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, USA. upul_bandarage@vrtx.com
Upul K
UK
Bandarage
Tiansheng
T
Wang
Jon H
JH
Come
Emanuele
E
Perola
Yunyi
Y
Wei
B Govinda
BG
Rao
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D018360:Crystallography, X-Ray; D015195:Drug Design; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D007527:Isoenzymes; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D013450:Sulfones; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein