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

Boshi Huang; Xinhao Liu; Ye Tian; Dongwei Kang; Zhongxia Zhou; Dirk Daelemans; Erik De Clercq; Christophe Pannecouque; Peng Zhan; Xinyong Liu

doi:10.1016/j.bmcl.2018.03.012

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. Epub 2018 Mar 5.

Authors

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: [email protected].
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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkynes
Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / metabolism
Anti-HIV Agents / pharmacology*
Benzoxazines / pharmacology
Cell Line, Tumor
Cyclopropanes
HIV Reverse Transcriptase / antagonists & inhibitors
HIV-1 / drug effects
HIV-1 / genetics
Humans
Hydrolysis
Mutation
Nevirapine / pharmacology
Nitriles
Prodrugs / chemical synthesis
Prodrugs / metabolism
Prodrugs / pharmacology*
Pyridazines / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / metabolism
Pyrroles / pharmacology*
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / metabolism
Reverse Transcriptase Inhibitors / pharmacology

Substances

Alkynes
Anti-HIV Agents
Benzoxazines
Cyclopropanes
Nitriles
Prodrugs
Pyridazines
Pyrimidines
Pyrroles
Reverse Transcriptase Inhibitors
etravirine
Nevirapine
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase
efavirenz