Investigation of the Bioactive Conformation of Histamine H3 Receptor Antagonists by the Cyclopropylic Strain-Based Conformational Restriction Strategy
详细信息 查看全文
- 作者：Mizuki Watanabe ; Takatsugu Hirokawa ; Takaaki Kobayashi ; Akira Yoshida ; Yoshihiko Ito ; Shizuo Yamada ; Naoki Orimoto ; Yasundo Yamasaki ; Mitsuhiro Arisawa ; Satoshi Shuto
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：May 13, 2010
- 年：2010
- 卷：53
- 期：9
- 页码：3585-3593
- 全文大小：1020K
- 年卷期：v.53,no.9(May 13, 2010)
- ISSN：1520-4804
文摘
We previously identified the highly potent histamine H3 receptor antagonists (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane (1) and its enantiomer ent-1. Although the conformations of 1 and ent-1 are restricted by the central cyclopropane ring, the 2-(4-chlorobenzylamino)ethyl side chain essential for the H3 receptor binding may somewhat freely rotate. To investigate the bioactive conformation, the 1′-ethyl-substituted derivatives 2a and 2b and their enantiomers ent-2a and ent-2b were designed as side chain conformation-restricted analogues of 1 and ent-1, based on the cyclopropylic strain. These compounds were synthesized, and their analysis by NMR and calculations suggested that the side chain moiety was effectively restricted in a syn-form or an anti-form by the cyclopropylic strain as expected. Pharmacological evaluation and docking simulation showed that the bioactive conformations of 1 and ent-1 appear to be the syn-form and the anti-form, respectively. Thus, the cyclopropylic strain can be effectively used for conformational restriction of the side chain moiety of cyclopropane compounds.