- 著者
- 味澤 幸義 赤羽 健司 赤羽 増夫 佐藤 和明 玉井 哲郎 斉藤 勝 田中 信之 鎌田 晃爾 小林 通洋
- 出版者
- 公益社団法人日本薬学会
- 雑誌
- 藥學雜誌 = Journal of the Pharmaceutical Society of Japan (ISSN:00316903)
- 巻号頁・発行日
- vol.116, no.9, pp.735-747, 1996-09-25
- 参考文献数
- 13
A number of benzimidazole derivatives were synthesized and tested for cholecystokinin A (CCK-A) receptor inhibitory activity in order to study structure-activity relationships. Significant CCK-A receptor inhibitory activities were found in the compounds having carboxyl or tetrazolyl group. As the most preferred compound, 4-(5,6-dichlorobenzimidazol-2-yl)-N-(3-methoxypropyl)-N-pentylglutaramic acid (4g) was selected.
- 著者
- 赤羽 健司 永野 泰夫 梅山 秀明
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.37, no.1, pp.86-92, 1989-01-25 (Released:2008-03-31)
- 参考文献数
- 26
- 被引用文献数
- 4 8
Two empirical indices accounting for the hydrophobic interaction are described. The first index is a "hydrophobic field-effect (Hf) index, "which indicates the hydrophobic nature of the binding site of a host molecule such as an enzyme, and the second index is a "hydrophobic correlation (Hc) index", which indicates the hydrophobic correspondency between a host molecule and its guest molecule such as a ligand. Furthermore, a method to calculate the surface area of a molecule is described, in which the molecular surface is treated as a set of area-preserving spherical triangles. The hydrophobic effects on the interaction between papain and its inhibitor benzyloxycarbonyl-L-phenylalanyl-L-alanyl-methylene (Z-Phe-Ala-CH2-), which is covalently bound to catalytic Cys Sγ of the enzyme, were investigated by using these indices. It is quantitatively shown that the binding sites interacting with the benzene rings of P2 Phe and P3 Z are more hydrophobic, while the site of the carbonyl group of P1 Ala is more hydrophilic. The substrate specificity of papain can be explained in part by these indices. Both the Hc and Hf indices are visualized by using computer graphics. These indices would be useful as quantitative structure-activity relationship (QSAR) parameters.
- 著者
- 味澤 幸義 赤羽 健司 赤羽 増夫 佐藤 和明 玉井 哲郎 斉藤 勝 田中 信之 鎌田 晃爾 小林 通洋
- 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.116, no.9, pp.735-747, 1996-09-25 (Released:2008-05-30)
- 参考文献数
- 13
- 被引用文献数
- 1 1
A number of benzimidazole derivatives were synthesized and tested for cholecystokinin A (CCK-A) receptor inhibitory activity in order to study structure-activity relationships. Significant CCK-A receptor inhibitory activities were found in the compounds having carboxyl or tetrazolyl group. As the most preferred compound, 4-(5, 6-dichlorobenzimidazol-2-yl)-N-(3-methoxypropyl)-N-pentylglutaramic acid (4g) was selected.
- 著者
- 赤羽 健司 上條 哲聖 飯塚 欣二 田口 武夫 小林 義郎 木曽 良明 梅山 秀明
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.36, no.9, pp.3447-3452, 1988-09-25 (Released:2008-03-31)
- 参考文献数
- 31
- 被引用文献数
- 3 4
The structure-activity relationship of acyl-His-trifluorinated leucinol derivatives as inhibitors of human renal renin is discussed based upon the tertiary structure of human renin, which was deduced from the crystal structure of penicillopepsin by assuming structural similarity. The structural requirements for the inhibitors and possible interactions at the renin binding site are discussed.
- 著者
- 飯塚 欣二 上條 哲聖 原田 弘 赤羽 健司 久保田 哲弘 島岡 巌 梅山 秀明 木曽 良明
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.36, no.6, pp.2278-2281, 1988-06-25 (Released:2008-03-31)
- 参考文献数
- 11
- 被引用文献数
- 4 4
New human renin inhibitors were designed from transition-state analogues of angiotensinogen, synthesized and evaluated. The peptide derovative, which contained 1-naphthylmethylsuccinylamide residue (P3) with a retro-inverso amide bond and a norstatine isoamylamide residue (P1-P1'), was stable to proteases and had potent human renin inhibitory activity. This compact inhibitor exhibited hypotension when administered orally to a monkey.
- 著者
- 飯塚 欣二 上條 哲聖 原田 弘 赤羽 健司 久保田 哲弘 江藤 裕夫 島岡 厳 椿 敦 村上 真 山口 敏章 伊與部 亮 梅山 秀明 木曽 良明
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.38, no.9, pp.2487-2493, 1990-09-25 (Released:2008-03-31)
- 参考文献数
- 33
- 被引用文献数
- 7 11
The synthesis and the structure-activity relationships of renin inhibitors designed from the angiotensinogen transition state are described. These inhibitors contained residues modified at P1-P1, , P2, and P4-P3. Decrease in the size of side chain alkyl group in norstatine analog at P1 diminished the inhibitory activities of the compounds. Compound 5j, which contained valine residue instead of histidine residue at P2, inhibited potently cathepsin D (IC50=6.0×10-9 M) and pepsin (IC50=3.5×10-7 M) to the same extent as renin (IC50=8.5×10-10 M), and thus was not specific for renin. The reduction of the β-carbonyl group to methylene group in β-carbonylpropionyl residue at P4-P3 decreased the potency about 2 orders against human renin (5i : IC50=1.1×10-7 M vs. 1 : IC50=2.4 ×10-9 M). These results confirmed the rationality of our analysis of the interaction between an orally potent human renin inhibitor 1 and the active site of human renin using modeling techniques, showing that 1 fits the active site of renin favorably. The experimental details of the synthesis are presented.