Thaisrivongs S, Tomasselli A G, Moon J B, Hui J, McQuade T J, Turner S R, Strohbach J W, Howe W J, Tarpley W G, Heinrikson R L
Department of Medicinal Chemistry, Upjohn Company, Kalamazoo, Michigan 49001.
J Med Chem. 1991 Aug;34(8):2344-56. doi: 10.1021/jm00112a005.
The peptidomimetic template and the dihydroxyethylene isostere insert that were applied successfully to the design of renin inhibitors have been extended to the related protease from human immunodeficiency virus (HIV). The present report describes the structure-activity study leading to the identification of an inhibitor with a Ki of less than 1 nM for the HIV type-1 protease (compound II). This compound, containing a diol insert, is highly effective in blocking polyprotein processing in in vitro cell culture assays. Results obtained from kinetic analysis, studies of the stereochemistry of the insert, and modeling have led to insights as to the requisites involved in the active site-inhibitor interaction.
已成功应用于肾素抑制剂设计的拟肽模板和二羟基乙烯电子等排体，已扩展至人类免疫缺陷病毒（HIV）的相关蛋白酶。本报告描述了结构活性研究，该研究导致鉴定出一种对1型HIV蛋白酶的抑制常数（Ki）小于1 nM的抑制剂（化合物II）。这种含有二醇插入基团的化合物在体外细胞培养试验中能高效阻断多蛋白加工。动力学分析、插入基团立体化学研究和建模所得结果，为活性位点与抑制剂相互作用的必要条件提供了深入见解。
