逆转录酶
药代动力学
逆转录酶抑制剂
核苷
化学
溶解度
核苷逆转录酶抑制剂
磷酸盐
铅化合物
效力
人类免疫缺陷病毒(HIV)
水溶性
药理学
药品
体内
生物化学
体外
病毒学
生物
核糖核酸
有机化学
生物技术
基因
作者
Jing-Bo Wang,Meng-Di Ma,Nan Lu,Yu-Zhuo Yang,Jinxuan Yang,Yiming Li,Cong-Qiang Xie,Ning-Yu Ma,Rong‐Hua Luo,Yueping Wang,Liu‐Meng Yang,Hongbin Zhang,Yong‐Tang Zheng,Yan‐Ping He
摘要
To improve the water solubility of anti-human immunodeficiency virus (HIV) agent DB02, an excellent non-nucleoside reverse-transcriptase inhibitor (NNRTI) obtained in our previous efforts, we designed and synthesized four phosphate derivatives of DB02 based on the molecular model of DB02 with RT. Here, the antiviral activity of these four derivatives was detected, leading to the discovery of compound P-2, which possessed a superior potency to the lead compound DB02 against wild-type HIV-1 and a variety of HIV-resistant mutant viruses significantly. Furthermore, the water solubility of P-2 was nearly 17 times higher than that of DB02, and the pharmacokinetic test in rats showed that P-2 demonstrate significantly improved oral bioavailablity of 14.6%. Our study showed that the introduction of a phosphate ester group at the end of the C-2 side chain of DB02 was beneficial to the improvement of its antiviral activity and pharmacokinetic properties, which provided a promising lead for the further development of S-DACOs type of NNRTIs.
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