Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Bioorg Med Chem Lett. 2012 Jul 1;22(13):4281-7. doi: 10.1016/j.bmcl.2012.05.024. Epub 2012 May 17.
The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.
本文描述了胃饥饿素受体的螺环哌啶氮杂环丁烷反向激动剂的发现。详细介绍了这些化合物相关问题的特征和解决。高效的三步合成和结合测定被用作快速提高这类反向激动剂化合物效力和 ADMET 性质的主要手段。化合物 10n 具有分布的极性，形式为咪唑并噻唑乙酰胺和苯基三唑，其 logP 降低了一个单位，与命中分子 10a 相比，结合亲和力显著提高，为进一步优化这一系列化合物提供了支持。
