title: A new 4-(2-methylquinolin-4-ylmethyl)phenyl P1' group for the beta-amino hydroxamic acid derived TACE inhibitors.
abstract: A new P1' group for TACE inhibitors was identified by eliminating the oxygen atom in the linker of the original 4-(2-methylquinolin-4-ylmethoxy)phenyl P1' group. Incorporation of this 4-(2-methylquinolin-4-ylmethyl)phenyl group onto different beta-aminohydroxamic acid cores provided compound 18, which demonstrated potent porcine TACE (p-TACE) and human whole blood activity, excellent PK properties, and good selectivity against a variety of MMPs.
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. xiao-tao.chen@bms.com
authors.forename: Xiao-Tao
authors.initials: XT
authors.lastname: Chen
authors.forename: Bahman
authors.initials: B
authors.lastname: Ghavimi
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Corbett
authors.forename: Chu-Biao
authors.initials: CB
authors.lastname: Xue
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Mingxin
authors.initials: M
authors.lastname: Qian
authors.forename: Krishna G
authors.initials: KG
authors.lastname: Vaddi
authors.forename: David D
authors.initials: DD
authors.lastname: Christ
authors.forename: Karl D
authors.initials: KD
authors.lastname: Hartman
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ribadeneira
authors.forename: James M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D000072198:ADAM17 Protein; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D010100:Oxygen / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat; D010100:Oxygen