19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides ( H 1 - H 19 ) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides ( J 1 - J 5 ) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the β 2 -adrenergic receptor (β 2 AR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at β 2 AR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against β 2 AR than Cmpd-15, the first reported β 2 AR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for β 2 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 2 AR NAM.
We designed and synthesized 27 new amide and dipeptide derivatives containing a substituted phenylalanine as negative allosteric modulators (NAMs) for the beta-2 adrenergic receptor (β2AR). These analogs aimed to improve the activity of our lead compound, Cmpd-15, by introducing variations in three key regions: the meta-bromobenzyl methylbenzamide (S1), para-formamidophenylalanine (S2), and 1-cyclohexyl-1-phenylacetyl (S3) groups. The synthesis involved the Pd-catalyzed β-C(sp3)-H arylation of N-acetylglycine with 1-iodo-4-substituent-benzenes as the key step. GloSensor cAMP accumulation assay revealed that six analogs (A1, C5, C6, C13, C15 and C17) surpass Cmpd-15 in β2AR allosteric function. This highlights the crucial role of the S1 region (meta-bromobenzyl methylbenzamide) in β2AR allostery while suggesting potential replaceability of the S2 region (para-formamidophenylalanine). These findings serve as a valuable springboard for further optimizing Cmpd-15, potentially leading to smaller, more active, and more stable β2AR-targeting NAMs.
Kaicheng Meng,Paul Shim,Qingtin Wang,Shuai Zhao,Ting Gu,Alem W. Kahsai,Seungkirl Ahn,Xin Chen
The β 2 -adrenergic receptor (β 2 AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the β 2 AR. Herein we report in details the design, synthesis and structure-activity relationships (SAR) of seven Cmpd-15 derivatives. Furthermore, we provide in a dose-response paradigm, the details of the effects of these derivatives in modulating agonist-induced β 2 AR activities (G-protein-mediated cAMP production and β-arrestin recruitment to the receptor) as well as the binding affinity of an orthosteric agonist in radio-ligand competition binding assay. Our results show that some modifications, including removal of the formamide group in the para -formamido phenylalanine region and bromine in the meta -bromobenzyl methylbenzamide region caused dramatic reduction in the functional activity of Cmpd-15. These SAR results provide valuable insights into the mechanism of action of the NAM Cmpd-15 as well as the basis for future development of more potent and selective modulators for the β 2 AR based on the chemical scaffold of Cmpd-15.
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