Structure-Activity Studies on Triazolothienodiazepine Derivaties as Platelet-Activating Factor Antagonists

• Published in: Chemical & pharmaceutical bulletin Vol. 39; no. 12; pp. 3215 - 3220
• Main Authors: MIYAZAWA, Shuhei, OKANO, Kazuo, SHIMOMURA, Naoyuki, CLARK, Richard S. J., KAWAHARA, Tesuya, ASANO, Osamu, YOSHIMURA, Hiroyuki, MIYAMOTO, Mituaki, SAKUMA, Yoshinori, MURAMOTO, Kenzo, OBAISHI, Hirosi, HARADA, Koukichi, KAJIMA, Takashi, YAMADA, Kouji, TSUNODA, Hajime, KATAYAMA, Satoshi, ABE, Shinya, ASAKAWA, Naoki, SOUDA, Shigeru, HORIE, Tohru, SATO, Tadashi, MACHIDA, Yoshimasa, KATAYAMA, Kouichi, YAMATSU, Isao
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 25-12-1991; Japan Science and Technology Agency
• Subjects: E6123; PAF antagonist; platelet activating factor (PAF); triazolothienodiazepine
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.39.3215

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.