Discovery of beta-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors.
Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation.
Duan
James J-W
JJ
Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. james.duan@bms.com
Chen
Lihua
L
Lu
Zhonghui
Z
Xue
Chu-Biao
CB
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Qian
Mingxin
M
Wasserman
Zelda R
ZR
Vaddi
Krishna
K
Christ
David D
DD
Trzaskos
James M
JM
Newton
Robert C
RC
Decicco
Carl P
CP
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D004285:Dogs; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine
D001549:Benzamides; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat