Synthesis and activity of quinolinylmethyl P1' alpha-sulfone piperidine hydroxamate inhibitors of TACE.
A series of alpha-sulfone piperidine hydroxamate TACE inhibitors 11a-n bearing a quinolinyl methyl P1' group was prepared, and their activity was compared to analogous alpha- and beta-sulfone piperidine hydroxamates with a butynyloxy P1' group. The quinolinyl methyl P1' group affords increased inhibitory enzyme activity relative to the corresponding butynyloxy P1' analogs in the alpha-sulfone piperidine hydroxamate series, and greater selectivity than the corresponding butynyloxy P1' analogs in the beta-sulfone piperidine hydroxamate series.
Zhang
Chunchun
C
Chemical and Screening Science, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. zhangc9@wyeth.com
Lovering
Frank
F
Behnke
Mark
M
Zask
Arie
A
Sandanayaka
Vincent
V
Sun
Linhong
L
Zhu
Yi
Y
Xu
Weixin
W
Zhang
Yuhua
Y
Levin
Jeremy I
JI
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry*
D006877:Hydroxamic Acids; D010880:Piperidines; D011480:Protease Inhibitors; D013450:Sulfones; C032727:piperidine; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse