Yohimbine derivatives containing carboxylic acid and ester bioisosteres as potent ADRA2A antagonists.

The α2A-adrenergic receptor (ADRA2A) has emerged as a promising target for precision medicine in metabolic and vascular disorders. However, the clinical translation of the prototypical antagonist, yohimbine, is hindered by poor subtype selectivity, leading to ADRA1A-mediated cardiovascular adverse events, and rapid, highly variable CYP2D6-mediated hepatic clearance. To overcome these liabilities, we designed and synthesized a novel series of yohimbine analogues by replacing the metabolically labile methyl carboxylate with potentially stable isosteric five-membered heterocycles or a nitrile group. Structure-activity relationship profiling revealed that while acidic bioisosteres yielded inactive compounds, non-ionizable methyl carboxylate bioisosteres exhibited robust ADRA2A antagonism with successfully abolished ADRA1A affinity. Notably, the 3-methyl-1,2,4-oxadiazole derivative 5 demonstrated highly potent ADRA2A antagonism (IC50 = 34 nM), exceptional off-target selectivity, and improved in vivo systemic exposure. Conversely, the 1,3-oxazole derivative 4 maintained favorable selectivity and metabolic stability while displaying a ∼20-fold reduction in membrane permeability, indicating a peripherally restricted profile. This bioisosteric strategy establishes a versatile chemical roadmap for developing highly selective, pharmacokinetically tunable ADRA2A modulators devoid of off-target cardiovascular risks.