title: 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-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4' ,3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (35(+)-isomer, E6123) was selected from among the compounds synthesized as a candidate for clinical study.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyazawa
authors.forename: K
authors.initials: K
authors.lastname: Okano
authors.forename: N
authors.initials: N
authors.lastname: Shimomura
authors.forename: R S
authors.initials: RS
authors.lastname: Clark
authors.forename: T
authors.initials: T
authors.lastname: Kawahara
authors.forename: O
authors.initials: O
authors.lastname: Asano
authors.forename: H
authors.initials: H
authors.lastname: Yoshimura
authors.forename: M
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Sakuma
authors.forename: K
authors.initials: K
authors.lastname: Muramoto
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C068033:E 6123