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.