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

19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (H-H) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides (J-J) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the β-adrenergic receptor (βAR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at βAR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against βAR than Cmpd-15, the first reported βAR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for βAR. 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 βAR NAM.