Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
J Med Chem. 2010 May 13;53(9):3585-93. doi: 10.1021/jm901848b.
We previously identified the highly potent histamine H(3) 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 H(3) 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.
我们先前鉴定了强效的组胺 H（3）受体拮抗剂 (1R,2S)-2-[2-(4-氯苄基氨基)乙基]-1-(1H-咪唑-4-基)环丙烷（1）及其对映异构体 ent-1。尽管 1 和 ent-1 的构象受到中环丙烷环的限制，但对于 H（3）受体结合至关重要的 2-(4-氯苄基氨基)乙基侧链可能会有些自由旋转。为了研究生物活性构象，我们基于环丙基张力，设计了 1'-乙基取代衍生物 2a 和 2b 及其对映异构体 ent-2a 和 ent-2b，作为 1 和 ent-1 的侧链构象限制类似物。这些化合物被合成，并通过 NMR 和计算进行分析，结果表明侧链部分如预期的那样被环丙基张力有效地限制在顺式或反式构象中。药理学评价和对接模拟表明，1 和 ent-1 的生物活性构象分别为顺式和反式。因此，环丙基张力可有效地用于限制环丙烷化合物的侧链部分的构象。
