Synthesis and SAR of diazepine and thiazepine TACE and MMP inhibitors.
Potent and selective TACE and MMP inhibitors utilizing the diazepine and thiazepine ring systems were synthesized and evaluated for biological activity in in vitro and in vivo models of TNF-alpha release. Oral activity in the mouse LPS model of TNF-alpha release was seen. Efficacy in the mouse collagen induced arthritis model was achieved with diazepine 20.
Zask
Arie
A
Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. zaska@wyeth.com
Kaplan
Joshua
J
Du
XueMei
X
MacEwan
Gloria
G
Sandanayaka
Vincent
V
Eudy
Nancy
N
Levin
Jeremy
J
Jin
Guixian
G
Xu
Jun
J
Cummons
Terri
T
Barone
Dauphine
D
Ayral-Kaloustian
Semiramis
S
Skotnicki
Jerauld
J
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D001381:Azepines; D061965:Matrix Metalloproteinase Inhibitors; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse