Synthesis and phosphodiesterase 5 inhibitory activity of novel phenyl ring modified sildenafil analogues Original Research Article

New sildenafil analogues containing an ether ring fused into the phenyl moiety, 6a–d and 7a–d, were efficiently synthesized from the readily available starting materials, 1a–d and 2, in five steps. Ab initio calculations indicated that introduction of a cyclic ether to the phenyl group might enhance the co-planarity of the molecule. The torsional angles were calculated to be 2−3° for the 5-membered cyclic ether derivatives, 6a, 6c, 7a, and 7c, and 12−16° for the 6-membered ones, 6b, 6d, 7b, and 7d. On the other hand, sildenafil showed the least co-planarity with the torsional angle of 23° compared with the target compounds, 6a–d and 7a–d. In the enzyme assay, however, the in vitro PDE 5 inhibitory activity was found out to be inversely related to the degree of co-planarity. In other words, the least planar sildenafil showed the highest activity, and the most planar 5-membered cyclic ether derivatives were least active by 100–200-fold compared with sildenafil. Our study clearly demonstrated that the open chain 2′-alkoxy group of the phenyl ring, although less effective for inducing the co-planarity, seemed to act as a much better lipophilic requirement than the cyclic alkoxy moiety.