Allosteric Inhibition of the β₂‐Adrenergic Receptor: Design and Synthesis of Cmpd‐15 Analogs

Abstract

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.