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.
摘要：
已设计并合成了19种1-苄基-3-芳基吡唑-5-甲酰胺衍生物（H1-H19）和5种1-苄基-5-芳基吡唑-3-甲酰胺衍生物（J1-J5），作为潜在的负变构调节剂（NAMs）用于β2-肾上腺素能受体（β2AR）。在β2AR的经典G蛋白依赖性信号通路上筛选了新的吡唑衍生物。大多数1-苄基-3-芳基-吡唑-5-甲酰胺衍生物比Cmpd-15（首次报道的β2ARNAM）对β2AR显示出更强的变构拮抗活性。然而,1-苄基-5-芳基吡唑-3-甲酰胺衍生物对β2AR表现出非常差的或甚至没有变构拮抗活性。此外，活性吡唑衍生物具有比Cmpd-15相对更好的药物样特征。一起来看,我们发现了一系列1-苄基-3-芳基吡唑-5-甲酰胺衍生物作为β2ARNAM的新型支架。
