In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition. Our main purpose was to find a more soluble compound based on the WAY207024 lead with nanomolar potency to inhibit the GnRH receptor. A late stage diversification by the use of click chemistry was, furthermore developed to allow for expansion of the library in future optimisations. All compounds were tested in a functional assay to determine the individual potency of inhibiting stimulation of the receptor by the endogenous agonist GnRH. In conclusion, we found that compound 8a showed improved solubility compared to WAY207024 and nanomolar affinity to GnRH receptor.

中文翻译：

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促性腺激素释放激素（GnRH）受体的小分子哌嗪基-苯并咪唑拮抗剂

在该通信中，我们报告释放基于2-（4-激素受体人促性腺激素小分子拮抗剂的文库的合成和表征叔丁基苯基）-4-哌嗪基-苯并咪唑骨架通过铜-催化的叠氮化物炔环。我们的主要目的是找到一种基于WAY207024铅的可溶化合物，其具有纳摩尔浓度的抑制GnRH受体的能力。此外，还开发了通过使用点击化学技术来实现后期多样化的方法，以允许在将来的优化中扩展库。在功能测定中测试了所有化合物，以确定内源激动剂GnRH抑制受体刺激的个体效力。总之，我们发现化合物8a 与WAY207024相比具有更好的溶解度，对GnRH受体的纳摩尔亲和力更高。