Chemical Biology Laboratory, and ‡HIV Drug Resistance Program, Center for Cancer Research, NCI at Frederick, National Institutes of Health , Building 376, Boyles Street, P.O. Box B, Frederick, Maryland 21702, United States.
J Med Chem. 2014 Jun 26;57(12):5190-202. doi: 10.1021/jm5001908. Epub 2014 Jun 16.
There are currently three HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) approved by the FDA for the treatment of AIDS. However, the emergence of drug-resistant mutants emphasizes the need to develop additional agents that have improved efficacies against the existent resistant mutants. As reported herein, we modified our recently disclosed 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN inhibitors to develop compounds that have improved efficacies against recombinant IN in biochemical assays. These new compounds show single-digit nanomolar antiviral potencies against HIV vectors that carry wild-type (WT) IN in a single round replication assay and have improved potency against vectors harboring the major forms of drug resistant IN mutants. These compounds also have low toxicity for cultured cells, which in several cases, results in selectivity indices (CC50/EC50) of greater than 10000. The compounds have the potential, with additional structural modifications, to yield clinical agents that are effective against the known strains of resistant viruses.
目前，FDA 批准了三种 HIV-1 整合酶（IN）链转移抑制剂（INSTI）用于治疗艾滋病。然而，耐药突变体的出现强调了需要开发具有更高疗效的额外药物来对抗现有的耐药突变体。本文报道了对最近公开的 1-羟基-2-氧代-1,2-二氢-1,8-萘啶-3-甲酰胺 IN 抑制剂进行修饰，以开发对重组 IN 在生化测定中具有更高疗效的化合物。这些新化合物在单次复制测定中对携带野生型（WT）IN 的 HIV 载体具有个位数纳摩尔的抗病毒效力，并且对携带主要形式耐药 IN 突变体的载体具有更高的效力。这些化合物对培养细胞的毒性也较低，在某些情况下，选择性指数（CC50/EC50）大于 10000。通过进一步的结构修饰，这些化合物有可能产生针对已知耐药病毒株有效的临床药物。
