ABSTRACT
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.
Subject(s)
Azepines/chemistry , Azepines/pharmacology , Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/antagonists & inhibitors , ADAM Proteins , ADAM17 Protein , Animals , Azepines/chemical synthesis , Female , Mice , Mice, Inbred BALB C , Models, Chemical , Molecular Structure , Structure-Activity RelationshipABSTRACT
Over 50 phenyl thiazolyl urea and carbamate derivatives were synthesized for evaluation as new inhibitors of bacterial cell-wall biosynthesis. Many of them demonstrated good activity against MurA and MurB and gram-positive bacteria including MRSA, VRE and PRSP. 3,4-Difluorophenyl 5-cyanothiazolylurea (3p) with clog P of 2.64 demonstrated antibacterial activity against both gram-positive and gram-negative bacteria.
