Design and synthesis of 3,5-disubstituted-1,2,4-oxadiazoles as potent inhibitors of phosphodiesterase4b2

A series of 3,5‐disubstituted‐1,2,4‐oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5‐disubstituted‐1,2,4‐oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC₅₀ = 5.28 μm ). Structure–activity relationship studies of 3,5‐disubstituted‐1,2,4‐oxadiazoles revealed that substituents 3‐cyclopentyloxy‐4‐methoxyphenyl group at 3‐position and cyclic ring bearing heteroatoms at 5‐position are important for activity. Molecular modeling study of the 3,5‐disubstituted‐1,2,4‐oxadiazoles with PDE4B has shown similar interactions of 3‐cyclopentyloxy‐4‐methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3‐(3‐Cyclopentyloxy‐4‐methoxyphenyl)‐5‐(piperidin‐4‐yl)‐1,2,4‐oxadiazole ( 9a ) exhibited good analgesic and antiinflammatory activities in formalin‐induced pain in mice and carrageenan‐induced paw edema model in rat.