ABSTRACT
A series of glycolic and mandelic acid derivatives was synthesized and investigated for their factor Xa inhibitory activity. These analogues are highly potent and selective inhibitors against fXa. In a rabbit deep vein thrombosis model, compound 26 showed significant antithrombotic effects (81% inhibition of thrombus formation) at 1.1 microM plasma concentration following intravenous administration.
Subject(s)
Acetanilides , Amidines/chemistry , Amidines/pharmacology , Factor Xa Inhibitors , Mandelic Acids/chemistry , Phenylacetates/chemistry , Phenylacetates/pharmacology , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Amidines/chemical synthesis , Animals , Biological Availability , Blood Coagulation Tests , Drug Design , Drug Evaluation, Preclinical/methods , Fibrinolysin/antagonists & inhibitors , Inhibitory Concentration 50 , Injections, Intravenous , Phenylacetates/chemical synthesis , Rabbits , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/chemical synthesis , Structure-Activity Relationship , Venous Thrombosis/drug therapyABSTRACT
Porphyromonas gingivalis, a periodontal pathogen can invade primary cultures of gingival epithelial cells. This invasion was significantly inhibited (74-81%) by thapsigargin and 1,2-bis(2-aminophenoxy)ethane-N,N,N1,N1-tetraacetic acid, acetoxymethyl ester (BAPTA/AM), but not by EDTA or amiloride. Release of Ca2+ from an intracellular store and the subsequent increase in cytosolic [Ca2+] may, therefore, be involved in the invasion process, while Ca2+ influx is not. Moreover, cytosolic [Ca2+] was found to increase transiently in about 30% of gingival epithelial cells acutely exposed to P. gingivalis, but not in unexposed cells, or in cells exposed to noninvasive Escherichia coli. These findings indicate that P. gingivalis invasion of epithelial cells is correlated with activation of [Ca2+]-dependent host cell signaling systems.
