Alpha,beta-cyclic-beta-benzamido hydroxamic acids: novel templates for the design, synthesis, and evaluation of selective inhibitors of TNF-alpha converting enzyme (TACE).
Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability.
Department of Discovery Chemistry and Discovery Biology, Bristol-Myers Squibb Research and Development, Route 206 and Province Line Road, Princeton, NJ 08543-4000, USA. gott@cephalon.com
Gregory R
GR
Ott
Naoyuki
N
Asakawa
Zhonghui
Z
Lu
Rui-Qin
RQ
Liu
Maryanne B
MB
Covington
Krishna
K
Vaddi
Mingxin
M
Qian
Robert C
RC
Newton
David D
DD
Christ
James M
JM
Traskos
Carl P
CP
Decicco
James J-W
JJ
Duan
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat