著者

宮澤 修平 岡野 和夫 下村 直之 / 川原 哲也 浅野 修 吉村 寛幸 宮本 光明 佐久間 義範 村本 賢三 尾葉石 浩 原田 耕吉 梶間 隆 山田 浩司 角田 創 片山 敏 阿部 信也 浅川 直樹 左右田 茂 堀江 透 里 忠 町田 善正 片山 幸一 山津 功 Isao YAMATSU

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.39, no.12, pp.3215-3220, 1991-12-25 (Released:2008-03-31)

参考文献数

27

被引用文献数

6 9

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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.

著者

菅谷 幸子 吉葉 孝子 梶間 隆 石濱 泰

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.122, no.3, pp.237-246, 2002 (Released:2003-02-18)

参考文献数

15

被引用文献数

12 21

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We developed two methods for solubility screening of drug candidates in drug discovery. The first is a solution-precipitation (SP) method, in which the sample solutions are prepared by adding the drug solution in dimethylsulfoxide (DMSO) to buffers followed by filtering off the precipitate using 96-well filterplate. The second is a powder-dissolution (PD) method, in which the solid samples are dissolved to the buffer in the HPLC vial equipped with the filter membrane in the HPLC autosampler. An HPLC equipped with a photodiode array detector is used to measure the concentration of the sample solutions in both methods. The SP method was used for high throughput screening the solvating process of the candidates in aqueous solutions with lower sample consumption, and the PD method was used for screening both inter-molecular interaction in solid state and solvation in aqueous solution with more sample amount than that of SP method. Therefore, the solubility screening from early to final stage of lead optimization process would be successfully accomplished by using both methods complementarily.