Potent, exceptionally selective, orally bioavailable inhibitors of TNF-alpha Converting Enzyme (TACE): novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1' substituents.
Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.
Ott
Gregory R
GR
Departments of Discovery Chemistry and Discovery Biology, Bristol-Myers Squibb Research and Development, Rte 206 and Province Line Road, Princeton, NJ 08543, USA. gott@cephalon.com
Asakawa
Naoyuki
N
Lu
Zhonghui
Z
Anand
Rajan
R
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Vaddi
Krishna
K
Qian
Mingxin
M
Newton
Robert C
RC
Christ
David D
DD
Trzaskos
James M
JM
Duan
James J-W
JJ
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D004285:Dogs; D006207:Half-Life; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
D001549:Benzamides; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat