Synthesis and structure-activity relationship of a novel, achiral series of TNF-alpha converting enzyme inhibitors.
A novel series of achiral TNF-alpha converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11nM in a porcine TACE assay and inhibited TNF-alpha production in an LPS-stimulated whole blood assay with an IC(50) value of 23nM for the most potent one. They also have excellent selectivities over related metalloproteases including aggrecanases.
Gilmore
John L
JL
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. john.gilmore@bms.com
King
Bryan W
BW
Harris
Cathy
C
Maduskuie
Thomas
T
Mercer
Stephen E
SE
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Qian
Mingxin
M
Ribadeneria
Maria D
MD
Vaddi
Krishna
K
Trzaskos
James M
JM
Newton
Robert C
RC
Decicco
Carl P
CP
Duan
James J-W
JJ
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D002460:Cell Line; D003500:Cyclization; D006801:Humans; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011480:Protease Inhibitors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse