Synthesis and phosphodiesterase 5 inhibitory activity of novel phenyl ring modified sildenafil analogues
Synthesis and phosphodiesterase 5 inhibitory activity of novel phenyl ring modified sildenafil analogues
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DOI：
10.1016/s0968-0896(01)00055-4
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发表时间：
2001-06-01
影响因子：
3.5
通讯作者：
Lee, K
中科院分区：
文献类型：
--
作者：
Kim, DK;Lee, N;Lee, K
含有与苯基部分融合的醚环的新西地那非类似物 6a-d 和 7a-d，是由容易获得的起始原料 1a-d 和 2 分五个步骤有效合成的。从头计算表明，向苯基引入环醚可能会增强分子的共面性。经计算，5元环醚衍生物6a、6c、7a和7c的扭转角为2-3度，6元环醚衍生物6b、6d、7b和7d的扭转角为12-16度。另一方面，与目标化合物6a-d和7a-d相比，西地那非表现出最小的共面性，扭转角为23度。然而，在酶测定中，发现体外 PDE 5 抑制活性与共面程度成反比。换句话说，最平面的西地那非表现出最高的活性，而最平面的五元环醚衍生物的活性则比西地那非低100-200倍。我们的研究清楚地表明，苯环的开链 2'-烷氧基虽然对于诱导共面性不太有效，但似乎比环状烷氧基部分具有更好的亲脂性要求。 (C) 2001 Elsevier Science Ltd. 保留所有权利。
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.