Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 1: lead identification.
Rational design based on the broad spectrum MMP inhibitor CGS 27023A led to the identification of a novel series of cyclic succinate TACE inhibitors. As a mixture of two enantiomers, the lead compound 17b exhibited potent enzyme activity (IC(50)=8 nM) in the inhibition of porcine TNF-alpha converting enzyme (pTACE) and excellent selectivity over aggrecanase and MMP-1, -2 and -9.
Xue
Chu-Biao
CB
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. cxue@incyte.com
He
Xiaohua
X
Roderick
John
J
Corbett
Ronald L
RL
Duan
James J-W
JJ
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Newton
Robert C
RC
Trzaskos
James M
JM
Magolda
Ronald L
RL
Wexler
Ruth R
RR
Decicco
Carl P
CP
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
C097658:CGS 27023A; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D013386:Succinates; D013449:Sulfonamides; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein