Design and synthesis of 3,3-piperidine hydroxamate analogs as selective TACE inhibitors.
Structure-based methods were used to design beta-sulfone 3,3-piperidine hydroxamates as TACE inhibitors with the aim of improving selectivity for TACE versus MMP-13. Several compounds in this series were synthesized and evaluated in enzymatic and cell-based assays. These analogs exhibit excellent in vitro potency against isolated TACE enzyme and show good selectivity for TACE over the related metalloproteases MMP-2, -13, and -14.
Lombart
Henry-Georges
HG
Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. hglombart@wyeth.com
Feyfant
Eric
E
Joseph-McCarthy
Diane
D
Huang
Adrian
A
Lovering
Frank
F
Sun
LinHong
L
Zhu
Yi
Y
Zeng
Congmei
C
Zhang
Yuhua
Y
Levin
Jeremy
J
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D051722:ADAM Proteins; D000072198:ADAM17 Protein