A new 4-(2-methylquinolin-4-ylmethyl)phenyl P1' group for the beta-amino hydroxamic acid derived TACE inhibitors.
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.
Chen
Xiao-Tao
XT
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. xiao-tao.chen@bms.com
Ghavimi
Bahman
B
Corbett
Ronald L
RL
Xue
Chu-Biao
CB
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Qian
Mingxin
M
Vaddi
Krishna G
KG
Christ
David D
DD
Hartman
Karl D
KD
Ribadeneira
Maria D
MD
Trzaskos
James M
JM
Newton
Robert C
RC
Decicco
Carl P
CP
Duan
James J-W
JJ
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
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat; D010100:Oxygen