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

J Med Chem. 2024 Apr 25;67(8):6570-6584. doi: 10.1021/acs.jmedchem.4c00026. Epub 2024 Apr 13.

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 (EC50 = 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 (T1/2 = 5.09 h, F = 108.96%) compared that of DOR (T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents* / chemical synthesis
  • Anti-HIV Agents* / chemistry
  • Anti-HIV Agents* / pharmacokinetics
  • Anti-HIV Agents* / pharmacology
  • Dihydropyridines* / chemistry
  • Dihydropyridines* / pharmacokinetics
  • Dihydropyridines* / pharmacology
  • Drug Discovery
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / metabolism
  • HIV-1* / drug effects
  • Humans
  • Male
  • Mice
  • Molecular Docking Simulation*
  • Molecular Structure
  • Reverse Transcriptase Inhibitors* / chemical synthesis
  • Reverse Transcriptase Inhibitors* / chemistry
  • Reverse Transcriptase Inhibitors* / pharmacokinetics
  • Reverse Transcriptase Inhibitors* / pharmacology
  • Structure-Activity Relationship
  • Triazoles* / chemistry
  • Triazoles* / pharmacokinetics
  • Triazoles* / pharmacology

Substances

  • Triazoles
  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • Dihydropyridines
  • HIV Reverse Transcriptase