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

被引：0

作者：

Guo, Xue ^{[1
]}

Luo, Zhijie ^{[1
]}

Qi, Ying ^{[1
]}

Hei, Xiaoyuan ^{[1
]}

Zhang, Xin ^{[1
]}

Cao, Xuli ^{[1
]}

Qian, Mingcheng ^{[1
]}

Zhao, Shuai ^{[1
]}

Hou, Yanan ^{[1
]}

Chen, Xin ^{[1
]}

机构：

[1] Changzhou Univ, Sch Pharm, Changzhou 213164, Jiangsu, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2024年 / 108卷

基金：

中国国家自然科学基金;

关键词：

beta 2-Adrenergic receptor (beta 2 AR); Negative allosteric modulator; Pyrazole; Synthesis; Structure -activity relationships;

D O I：

10.1016/j.bmc.2024.117787

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (H1-H19) and 5 derivatives of 1-benzyl-5-arylpyrazole3-carboxamides (J1-J5) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the beta 2-adrenergic receptor (beta 2AR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at beta 2AR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against beta 2AR than Cmpd-15, the first reported beta 2AR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for beta 2AR. Furthermore, the active pyrazole derivatives have relative better drug-like profiles than Cmpd15. Taken together, we discovered a series of derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides as a novel scaffold of beta 2AR NAM.

引用

页数：14

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