Structure-activity relationships of thiadiazole agonists of the human secretin receptor

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

SLAS Discovery Pub Date : 2024-08-08 DOI:10.1016/j.slasd.2024.100176

Robert Ardecky , Daniela G. Dengler , Kaleeckal G. Harikumar , Mathew M. Abelman , Jiwen Zou , Bryan A. Kramer , Santhi Reddy Ganji , Steve Olson , Alina Ly , Nikhil Puvvula , Chen-Ting Ma , Raghuveer Ramachandra , Eduard A. Sergienko , Laurence J. Miller

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引用次数: 0

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.

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人类胰泌素受体噻二唑激动剂的结构-活性关系。

胰泌素受体激动剂具有治疗心血管、胃肠道和新陈代谢系统疾病的潜在用途，但目前尚未开发出具有临床活性的非肽类胰泌素受体激动剂。在目前的工作中，我们发现了一种具有这种药理特征的新的小分子先导化合物。我们围绕这个噻二唑支架制备了一个系统的结构-活性系列，并对其进行了表征，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。我们发现活性最强的候选化合物在血浆中相当稳定，尽管它会被肝微粒体代谢掉。这种化学探针应有助于体外研究，并需要进行体内药理活性测试。这可能是开发第一类口服活性泌乳素受体激动剂的重要线索，可用于多种疾病的治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

SLAS Discovery Chemistry-Analytical Chemistry

CiteScore

7.00

自引率

3.20%

发文量

审稿时长

39 days

期刊介绍： Advancing Life Sciences R&D: SLAS Discovery reports how scientists develop and utilize novel technologies and/or approaches to provide and characterize chemical and biological tools to understand and treat human disease. SLAS Discovery is a peer-reviewed journal that publishes scientific reports that enable and improve target validation, evaluate current drug discovery technologies, provide novel research tools, and incorporate research approaches that enhance depth of knowledge and drug discovery success. SLAS Discovery emphasizes scientific and technical advances in target identification/validation (including chemical probes, RNA silencing, gene editing technologies); biomarker discovery; assay development; virtual, medium- or high-throughput screening (biochemical and biological, biophysical, phenotypic, toxicological, ADME); lead generation/optimization; chemical biology; and informatics (data analysis, image analysis, statistics, bio- and chemo-informatics). Review articles on target biology, new paradigms in drug discovery and advances in drug discovery technologies. SLAS Discovery is of particular interest to those involved in analytical chemistry, applied microbiology, automation, biochemistry, bioengineering, biomedical optics, biotechnology, bioinformatics, cell biology, DNA science and technology, genetics, information technology, medicinal chemistry, molecular biology, natural products chemistry, organic chemistry, pharmacology, spectroscopy, and toxicology. SLAS Discovery is a member of the Committee on Publication Ethics (COPE) and was published previously (1996-2016) as the Journal of Biomolecular Screening (JBS).