新型氨基嘧啶选择性EP2受体拮抗剂的发现。

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2025-04-07 DOI:10.1002/cmdc.202500119

Olivier Corminboeuf, Isabelle Lyothier, Stefan Diethelm, Julien Pothier, Thierry Sifferlen, Davide Pozzi, Sylvia Richard-Bildstein, Hervé Siendt, Heinz Fretz, Christoph Boss, Lorenza Wyder, Sébastien Jeay, Ruben de Kanter, Carmela Gnerre, François Lehembre, Dominique S Meyer

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引用次数: 0

摘要

EP2是一种由前列腺素E2 （PGE2）激活的g蛋白偶联受体。通过EP2受体传递的信号已被证明在免疫紊乱或癌症等疾病的各种过程中发挥关键作用。我们已经确定了一类新的选择性EP2拮抗剂具有吸引力的体外和体内的概况。原始筛选命中的酰胺键被各种替代品取代。氨基嘧啶支架的引入产生了优异的效价。通过加入一个羧酸片段来改善其理化性质和ADME性质，从而使先导化合物29具有类似药物的性质。

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Discovery of Novel Aminopyrimidines as Selective EP2 Receptor Antagonists.

EP2 is a G-protein coupled receptor that is activated by Prostaglandin E2 (PGE2). Signaling through the EP2 receptor has been shown to play a key role in various processes involved in diseases such as immune disorders or cancer. We have identified a new class of selective EP2 antagonists with an attractive in vitro and in vivo profile. The amide bond in the original screening hit was replaced by various alternatives. Introduction of an aminopyrimidine scaffold resulted in excellent potency. Improvement of physicochemical and ADME properties was achieved by incorporation of a carboxylic acid moiety, resulting in lead compound 29 exhibiting drug-like properties.

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.