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

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.