Abstract：
Agonists of the secretin receptor have potential applications for diseases of the cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists of this receptor have yet been developed. In the current work, we have identified a new small molecule lead compound with this pharmacological profile. We have prepared and characterized a systematic structure-activity series around this thiadiazole scaffold to better understand the molecular determinants of its activity. We were able to enhance the in vitro activity and to maintain the specificity of the parent compound. We found the most active candidate to be quite stable in plasma, although it was metabolized by hepatic microsomes. This chemical probe should be useful for in vitro studies and needs to be tested for in vivo pharmacological activity. This could be an important lead toward the development of a first-in-class orally active agonist of the secretin receptor, which could be useful for multiple disease states.
摘要：
促胰液素受体激动剂对心血管疾病有潜在的应用,胃肠,和代谢系统，然而，尚未开发出具有临床活性的该受体的非肽基激动剂。在目前的工作中,我们已经确定了一种新的小分子先导化合物具有这种药理学特征。我们已经围绕该噻二唑支架制备并表征了系统的结构-活性系列，以更好地了解其活性的分子决定因素。我们能够增强体外活性并保持母体化合物的特异性。我们发现最活跃的候选物在血浆中相当稳定，尽管它被肝微粒体代谢。这种化学探针应该可用于体外研究，需要测试体内药理活性。这可能是开发一流的促胰液素受体口服活性激动剂的重要线索，这可能对多种疾病状态有用。
