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Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV-1 NNRTIs.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Apr 25; Vol. 67 (8), pp. 6570-6584. Date of Electronic Publication: 2024 Apr 13. - Publication Year :
- 2024
-
Abstract
- 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 <subscript>50</subscript> = 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 <subscript>1/2</subscript> = 5.09 h, F = 108.96%) compared that of DOR ( T <subscript>1/2</subscript> = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD <subscript>50</subscript> > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.
- Subjects :
- Humans
Structure-Activity Relationship
HIV Reverse Transcriptase antagonists & inhibitors
HIV Reverse Transcriptase metabolism
Animals
Male
Drug Discovery
Molecular Structure
Mice
HIV-1 drug effects
Triazoles chemistry
Triazoles pharmacology
Triazoles pharmacokinetics
Anti-HIV Agents pharmacology
Anti-HIV Agents chemistry
Anti-HIV Agents chemical synthesis
Anti-HIV Agents pharmacokinetics
Reverse Transcriptase Inhibitors pharmacology
Reverse Transcriptase Inhibitors chemistry
Reverse Transcriptase Inhibitors chemical synthesis
Reverse Transcriptase Inhibitors pharmacokinetics
Molecular Docking Simulation
Dihydropyridines chemistry
Dihydropyridines pharmacology
Dihydropyridines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38613773
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c00026