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

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 degrees for the 5-membered cyclic ether derivatives, 6a, 6c, 7a, and 7c, and 12-16 degrees 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 degrees 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 coplanarity. 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. (C) 2001 Elsevier Science Ltd. All rights reserved.