From Flat to 3D: Replacing Phenyl Rings with Saturated Bridged Bicyclic Mimetics to Mitigate Bioactivation and Optimize ADME Properties and Oral Bioavailability in Reverse Amide Orientation.

Replacing phenyl rings with saturated bridged bicyclic scaffolds can mitigate liabilities inherent in planar aromatic rings. We evaluated the retro-isosteric impact of phenyl-to-bridged bicyclic substitution on bioactivation and ADME/PK using phenyl prototype 2b that displayed rapid microsomal turnover, glutathione-adduct formation, high plasma protein binding, poor solubility, and modest oral bioavailability. Bridged bicyclic analogues abolished reactive metabolite formation and improved metabolic stability (2-6-fold), while bridgehead substitution delivered greater improvements (up to 58-fold). In mice, fluoro-BCHex improved bioavailability to 30%, whereas oxa-BCHex achieved 100% bioavailability with 10× higher exposure than 2b, consistent with enhanced microsomal stability, solubility, and permeability. MMP analysis revealed that amide reversal significantly reduced the MLM half-life, plasma fraction unbound, and solubility, while HLM t1/2 and permeability were unaffected. These findings position bridged bicycles as effective benzene mimetics for mitigating bioactivation with incremental ADME benefits, with bridgehead functionalization, heteroatom incorporation, and amide orientation as tunable handles for further ADME/PK optimization.