2. Academic Validation
  3. First discovery of a potential carbonate prodrug of NNRTI drug candidate RDEA427 with submicromolar inhibitory activity against HIV-1 K103N/Y181C double mutant strain

First discovery of a potential carbonate prodrug of NNRTI drug candidate RDEA427 with submicromolar inhibitory activity against HIV-1 K103N/Y181C double mutant strain

  • Bioorg Med Chem Lett. 2018 May 1;28(8):1348-1351. doi: 10.1016/j.bmcl.2018.03.012.
Boshi Huang 1,  Xinhao Liu 1,  Ye Tian 1,  Dongwei Kang 1,  Zhongxia Zhou 1,  Dirk Daelemans 2,  Erik De Clercq 2,  Christophe Pannecouque 2,  Peng Zhan 3,  Xinyong Liu 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
  • 2 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U.Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 29534929 DOI: 10.1016/j.bmcl.2018.03.012
Abstract

In the present work, we described the synthesis, Antiviral profiles and metabolic stability in human plasma of compound 6, a potential carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound 6 was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at nano- and submicromolar concentrations, respectively. Moreover, it displayed potent HIV-1 Reverse Transcriptase inhibitory activity (IC50 = 0.264 μM). Further stability test in human plasma showed that 6 could release its active form RDEA427 in a linearly time-independent manner, possibly acting as a potential prodrug.

Keywords

Anti-HIV activity; Carbonate prodrug; HIV-1 NNRTI; Metabolic stability; RDEA427.

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