Abstract:
: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 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.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Kim DK,Lee N,Lee JY,Ryu DH,Kim JS,Lee SH,Choi JY,Chang K,Kim YW,Im GJ,Choi WS,Kim TK,Ryu JH,Kim NH,Lee Kdoi
10.1016/s0968-0896(01)00055-4subject
Has Abstractpub_date
2001-06-01 00:00:00pages
1609-16issue
6eissn
0968-0896issn
1464-3391pii
S0968089601000554journal_volume
9pub_type
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