Kukla M J, Breslin H J, Pauwels R, Fedde C L, Miranda M, Scott M K, Sherrill R G, Raeymaekers A, Van Gelder J, Andries K
Janssen Research Foundation, Spring House, Pennsylvania 19477.
J Med Chem. 1991 Feb;34(2):746-51. doi: 10.1021/jm00106a040.
A series of 6-substituted 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-ones (9) have been synthesized and tested for their ability to inhibit the replication of the HIV-1 virus in MT-4 cells. Two synthetic methods are described, one of which allows the synthesis of single enantiomers of the final products. A structure-activity study was done within the series of compounds to determine the optimum group for the 6-position substitution and to determine whether the activity was enantiospecific at the 5-position, which was substituted with a methyl group. The best analogue, 9jj, inhibited HIV-1 with an IC50 of 4 microM, which is comparable to the activity level of DDI, a 2',3'-dideoxynucleoside-type structure undergoing clinical trials as an anti-AIDS therapy.
已合成了一系列6-取代的4,5,6,7-四氢-5-甲基咪唑并[4,5,1-jk][1,4]苯并二氮杂䓬-2(1H)-酮(9)，并测试了它们在MT-4细胞中抑制HIV-1病毒复制的能力。描述了两种合成方法，其中一种方法能够合成最终产物的单一对映体。在该系列化合物中进行了构效关系研究，以确定6-位取代的最佳基团，并确定在被甲基取代的5-位上活性是否具有对映体特异性。最佳类似物9jj对HIV-1的抑制IC50为4微摩尔，这与作为抗艾滋病疗法正在进行临床试验的2',3'-双脱氧核苷类结构的地丹诺辛的活性水平相当。
