5,6-dihydropyran-2-ones possessing various sulfonyl functionalities: Potent nonpeptidic inhibitors of HIV protease
5,6-dihydropyran-2-ones possessing various sulfonyl functionalities: Potent nonpeptidic inhibitors of HIV protease
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DOI：
10.1021/jm990281p
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发表时间：
2000-03-09
影响因子：
7.3
通讯作者：
Erickson, JW
中科院分区：
文献类型：
--
作者：
Boyer, FE;Prasad, JVNV;Erickson, JW
在以往SAR研究结果和分子模拟研究的基础上，合成了一系列具有在二氢吡喃-2-酮环系统的C-3苯环取代基的4-位上取代的各种磺酰基部分的化合物。加入磺酰基取代基试图填充额外的S-3'口袋，从而产生越来越有效的靶酶抑制剂。合成了所选化合物的外消旋体和对映体拆分品种。研究中的所有类似物都显示出与HIV蛋白酶的良好结合亲和力，并且几种化合物显示出具有非常好的抗病毒功效和安全范围。X射线晶体结构证实，磺酰胺和磺酸盐部分填充的S3'口袋的酶。然而，与拆分的未取代苯胺相比，另外的取代基没有提供改善的酶抑制或抗病毒活性。添加磺酰基部分取代似乎不能提供有利的药物动力学参数。在临床分离株中测试所选择的抑制剂的抗病毒活性，并且对所有测试的HIV-1毒株显示出与它们对野生型HIV-1相似的抗病毒活性。此外，抑制剂对显示出对当前市售蛋白酶抑制剂的抗性的HIV-1毒株显示出良好的抗病毒效力。
On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S-3' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S3' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1, In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.