HIV-1逆转录酶哒嗪酮非核苷抑制剂的发现与优化
Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase.
作者信息
Sweeney Zachary K, Dunn James P, Li Yu, Heilek Gabrielle, Dunten Pete, Elworthy Todd R, Han Xiaochun, Harris Seth F, Hirschfeld Donald R, Hogg J Heather, Huber Walter, Kaiser Ann C, Kertesz Denis J, Kim Woongki, Mirzadegan Taraneh, Roepel Michael G, Saito Y David, Silva Tania M P C, Swallow Steven, Tracy Jahari L, Villasenor Armando, Vora Harit, Zhou Amy S, Klumpp Klaus
机构信息
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
出版信息
Bioorg Med Chem Lett. 2008 Aug 1;18(15):4352-4. doi: 10.1016/j.bmcl.2008.06.072. Epub 2008 Jun 28.
A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
对一系列苄基哒嗪酮进行了评估，以确定其作为HIV-1非核苷类逆转录酶抑制剂（NNRTIs）的活性。该系列中的几个成员对野生型病毒和耐NNRTI病毒表现出良好的活性。通过表面等离子体共振光谱分析了抑制剂5a与HIV-RT的结合情况。在大鼠和狗身上对5a进行的药代动力学研究表明，该化合物在动物物种中具有良好的口服生物利用度。还描述了HIV-RT与抑制剂4c之间复合物的晶体结构。
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