title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Ott
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Asakawa
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Lu
authors.forename: Rajan
authors.initials: R
authors.lastname: Anand
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Krishna
authors.initials: K
authors.lastname: Vaddi
authors.forename: Mingxin
authors.initials: M
authors.lastname: Qian
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: David D
authors.initials: DD
authors.lastname: Christ
authors.forename: James M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
mesh_terms: 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
chemical_list: D001549:Benzamides; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat