Shruti Surendran, Sivashankaran Raju, Naveen Kalyani, Gaurav Saini, Joyson Nandha, Himangshu Bhowmik, Anil Rathod, S. Choubey, Bhuvaneshwaran Anandamoorthy, Sukanta Kumar Sahoo, Y.K. Gupta, Muthalagu Vetrichelvan, Anuradha Gupta, Salil D. Desai, Thanga Mariappan, Arvind Mathur, Prakash Vachaspati, Murugaiah A. M. Subbaiah
Abstract The increasing adoption of 3D sp3-hybridized bridged bicyclic moieties as saturated bioisosteres of benzene rings signifies a compelling evolution in modern medicinal chemistry, facilitated by recent synthetic advancements. Inspired by this, we evaluated the metabolic stability and other ADME profiles of various bridged bicyclic systems, comparing them to a monosubstituted benzene counterpart. Our findings indicate that these bicyclic scaffolds enhance metabolic stability, with further notable enhancements achieved by strategic structural modifications, such as fluorine substitution at the bridgehead sp3 carbon or incorporation of an oxygen atom within the bridge. Importantly, metabolite profiling revealed that these analogues effectively mitigate the formation of reactive metabolites, a critical liability of phenyl-containing compounds. Notably, the tested oxabicyclic match pairs demonstrated overall more favorable ADME profiles than the phenyl counterpart. These results collectively underscore the promising potential of bridged bicyclic systems to address key challenges in drug metabolism and ADME properties, thereby offering valuable insights for drug design.