{"title":"Structure optimization of Cmpd-15 as negative allosteric modulators for the β2-adrenergic receptor","authors":"Xue Guo , Zhijie Luo , Ying Qi, Xiaoyuan Hei, Xin Zhang, Xuli Cao, Mingcheng Qian, Shuai Zhao, Yanan Hou, Xin Chen","doi":"10.1016/j.bmc.2024.117787","DOIUrl":null,"url":null,"abstract":"<div><p>19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (<strong>H<sub>1</sub></strong>-<strong>H<sub>19</sub></strong>) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides (<strong>J<sub>1</sub></strong>-<strong>J<sub>5</sub></strong>) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the β<sub>2</sub>-adrenergic receptor (β<sub>2</sub>AR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at β<sub>2</sub>AR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against β<sub>2</sub>AR than Cmpd-15, the first reported β<sub>2</sub>AR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for β<sub>2</sub>AR. 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 β<sub>2</sub>AR NAM.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089624002013","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
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.