Structure-activity studies on triazolothienodiazepine derivatives as platelet-activating factor antagonists.
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.
Miyazawa
S
S
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Okano
K
K
Shimomura
N
N
Clark
R S
RS
Kawahara
T
T
Asano
O
O
Yoshimura
H
H
Miyamoto
M
M
Sakuma
Y
Y
Muramoto
K
K
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
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C068033:E 6123