Discovery of novel indole amide derivatives as allosteric inhibition of the β2-adrenergic receptor.

Abstract

We used the first reported allosteric antagonist of β2-adrenergic receptors (β2AR), Cmpd-15, as a lead compound. Employing the principles of scaffold hopping and bioisosterism, we designed and synthesized a series of indole amide derivatives. Allosteric antagonistic activity of these compounds on β2AR was assessed using a GloSensor™ cAMP accumulation assay, and a structure-activity relationship (SAR) analysis was carried out. Our findings revealed that the indole amide derivatives exhibited allosteric antagonism on the G protein signaling pathway of β2AR, effectively modulating the agonistic effect of the endogenous ligand isoproterenol (ISO) on β2AR. Notably, the allosteric activity of derivative M19 was 2.28 times that of the lead compound Cmpd-15, significantly expanding the structural diversity of the lead compound. Furthermore, the indole amide derivatives possess a simpler structural framework compared to Cmpd-15. Further investigation of the most active compound, M19, revealed that it exhibited no significant cytotoxicity. The solubility of M19 was superior to that of Cmpd-15, being approximately 7-fold higher. Moreover, M19 showed significantly improved metabolic stability in vitro compared with Cmpd-15. Collectively, M19 demonstrated markedly improved activity, drug-like properties, and safety profiles compared with Cmpd-15, highlighting its promising potential for further development.

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