Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV-1 NNRTIs.

Autor:	Sun Y; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China., Zhou Z; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China., Wang N; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China., Zhao F; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China., Liu Y; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China., Xu X; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China., Wang X; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China., Gou Z; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China., De Clercq E; Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), Leuven B-3000, Belgium., Pannecouque C; Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), Leuven B-3000, Belgium., Zhan P; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China.; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Jinan 250012, P.R. China., Kang D; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China.; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Jinan 250012, P.R. China., Liu X; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road ,Jinan ,Shandong 250012, P.R. China.; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Jinan 250012, P.R. China.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Apr 25; Vol. 67 (8), pp. 6570-6584. Date of Electronic Publication: 2024 Apr 13.
DOI:	10.1021/acs.jmedchem.4c00026
Abstrakt:	NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC 50 = 0.009-17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile ( T 1/2 = 5.09 h, F = 108.96%) compared that of DOR ( T 1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD 50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.
Databáze:	MEDLINE
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