Abstract Although naphthalene motifs are frequently encountered in drugs and lead compounds, their flat, sp 2 -rich nature and susceptibility to cytochrome P450-mediated metabolism often limit their developability. Here we report the study of derivatizable aryl-fused bicyclo3.1.1heptanes (BCHeps) as sp 3 -rich bioisosteric replacements for naphthalene and other fused bicyclic (hetero)aromatics, including underrepresented β-naphthyl units. The BCHeps were efficiently accessed via an intramolecular crossed 2+2 photocycloaddition enabled by visible light energy transfer and subsequently diversified to provide a range of different scaffolds. Here we show that the incorporation of BCHep-based naphthyl isosteres into the AhR antagonist ezutromid preserves key geometric exit vectors while reducing the fraction of sp 2 carbon atoms. Importantly, these analogues retain biological activity and display improved metabolic stability towards CYP1A-mediated metabolism. Solid-state structures, cellular assays and microsomal studies confirm that BCHep substitution mitigates reactive metabolite formation, validating aryl-fused BCHeps as true bioisosteric replacements for meta -substituted arenes and 2-naphthalenes.
Kerckhoffs et al. (Wed,) studied this question.