环状磺酰胺HIV-1蛋白酶抑制剂，其侧链跨度从P2/P2'到P1/P1'。

Cyclic sulfamide HIV-1 protease inhibitors, with sidechains spanning from P2/P2' to P1/P1'.

作者信息

Ax Anna, Schaal Wesley, Vrang Lotta, Samuelsson Bertil, Hallberg Anders, Karlén Anders

机构信息

Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.

出版信息

Bioorg Med Chem. 2005 Feb 1;13(3):755-64. doi: 10.1016/j.bmc.2004.10.042.

DOI:10.1016/j.bmc.2004.10.042

PMID:15653343

Abstract

Previous studies of HIV protease inhibitors have shown that it is possible to elongate the P1/P1' sidechains to reach the S3/S3' binding sites. By analogy, we expected that it would be possible to design inhibitors reaching between the S1/S1' and S2/S2' binding sites. Molecular modeling suggested that this could be achieved with appropriate ortho-substitution of the P2/P2' benzyl groups in our cyclic sulfamide inhibitors. Four different spacer groups were investigated. The compounds were smoothly prepared from tartaric acid in five steps and exhibit low to moderate activity, the most potent inhibitor possessing a Ki value of 0.53 microM.

摘要

先前对HIV蛋白酶抑制剂的研究表明，延长P1/P1'侧链以到达S3/S3'结合位点是可行的。以此类推，我们预计有可能设计出能到达S1/S1'和S2/S2'结合位点之间的抑制剂。分子模拟表明，在我们的环状磺酰胺抑制剂中，通过对P2/P2'苄基进行适当的邻位取代可以实现这一点。研究了四种不同的间隔基团。这些化合物由酒石酸分五步顺利制备，活性低至中等，最有效的抑制剂的Ki值为0.53微摩尔。