%0 Journal Article
%T Structure optimization of Cmpd-15 as negative allosteric modulators for the β2-adrenergic receptor.
%A Guo X
%A Luo Z
%A Qi Y
%A Hei X
%A Zhang X
%A Cao X
%A Qian M
%A Zhao S
%A Hou Y
%A Chen X
%J Bioorg Med Chem
%V 108
%N 0
%D 2024 Jun 15
%M 38838580
%F 3.461
%R 10.1016/j.bmc.2024.117787
%X 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.