Structure—Activity Studies on Triazolothienodiazepine Derivatives as Platelet-Activating Factor Antagonists

Abstract

A series of triazolodiazepines was synthesized and evaluated for anti-platelet activating factor (PAF) activities. Structure-activity relationship (SAR) studies on this series revealed that the introduction of a methyl group into the 8-position of the thienodiazepine nucleus can lead to a lengthening of the duration of action. Introduction of a methyl group produced an asymmetric center and the enantiomers so formed were separated with an optical resolving column. In the in vitro assay system, the (+ )-isomers displayed 50—200 times more potent anti-PAF activity than the (—)-isomers. After comparison of toxicology and pharmacokinetics, (+ )-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,ll-dimethyl-2,3,4,5-tetrahydro-8//-pyrido[4 ‘,3,:4,5]thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepine (35( + )-isomer, E6123) was selected from among the compounds synthesized as a candidate for clinical study. © 1991, The Pharmaceutical Society of Japan. All rights reserved.