Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses

Bioorg Med Chem Lett. 2014 Feb 1;24(3):917-22. doi: 10.1016/j.bmcl.2013.12.070. Epub 2013 Dec 24.

Abstract

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.

Keywords: HIV; Inhibitor; Non-nucleoside reverse transcriptase; Pyridone; Triazolinone.

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Cells, Cultured
  • Crystallography, X-Ray
  • Dogs
  • Drug Discovery*
  • Drug Resistance, Viral / drug effects*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Mutation
  • Pyridones / chemistry*
  • Pyridones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Triazoles / chemistry*
  • Triazoles / pharmacology*

Substances

  • Anti-HIV Agents
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • Triazoles
  • doravirine