Structure optimization of Cmpd-15 as negative allosteric modulators for the β2-adrenergic receptor

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2024-06-02 DOI:10.1016/j.bmc.2024.117787

Xue Guo , Zhijie Luo , Ying Qi, Xiaoyuan Hei, Xin Zhang, Xuli Cao, Mingcheng Qian, Shuai Zhao, Yanan Hou, Xin Chen

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引用次数: 0

Abstract

19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (H₁-H₁₉) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides (J₁-J₅) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the β₂-adrenergic receptor (β₂AR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at β₂AR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against β₂AR than Cmpd-15, the first reported β₂AR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for β₂AR. Furthermore, the active pyrazole derivatives have relative better drug-like profiles than Cmpd-15. Taken together, we discovered a series of derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides as a novel scaffold of β₂AR NAM.

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作为β2-肾上腺素能受体负异构型调节剂的 Cmpd-15 的结构优化

我们设计并合成了 19 种 1-苄基-3-芳基吡唑-5-羧酰胺衍生物（H1-H19）和 5 种 1-苄基-5-芳基吡唑-3-羧酰胺衍生物（J1-J5），这些衍生物可能成为 β2-肾上腺素能受体（β2AR）的负异位调节剂（NAMs）。新的吡唑衍生物是在β2AR的经典G蛋白依赖信号通路上进行筛选的。大多数 1-苄基-3-芳基吡唑-5-甲酰胺衍生物对 β2AR 的异构拮抗活性比首次报道的 β2AR NAM Cmpd-15 更强。然而，1-苄基-5-芳基吡唑-3-甲酰胺衍生物对 β2AR 的异构拮抗活性很低，甚至没有。此外，与 Cmpd-15 相比，活性吡唑衍生物具有更好的类药物特征。综上所述，我们发现了一系列 1-苄基-3-芳基吡唑-5-羧酰胺衍生物，它们是 β2AR NAM 的新型支架。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.