Molecular design and evaluation of aza-polycyclic carbamoyl pyridones as HIV-1 integrase strand transfer inhibitors

Bioorg Med Chem Lett. 2024 Oct 1:111:129902. doi: 10.1016/j.bmcl.2024.129902. Epub 2024 Jul 24.

Abstract

Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure-activity studies using these scaffolds resulted in several leads with promising properties.

Keywords: HIV integrase; INSTIs (integrase strand transfer inhibitors); Long-acting; Scaffold hopping.

MeSH terms

  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HIV Integrase Inhibitors* / chemical synthesis
  • HIV Integrase Inhibitors* / chemistry
  • HIV Integrase Inhibitors* / pharmacology
  • HIV Integrase* / metabolism
  • HIV-1* / drug effects
  • Humans
  • Integrases / chemistry
  • Integrases / metabolism
  • Integrases / pharmacokinetics
  • Molecular Structure
  • Pyridones* / chemical synthesis
  • Pyridones* / chemistry
  • Pyridones* / pharmacology
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • HIV Integrase
  • HIV Integrase Inhibitors
  • p31 integrase protein, Human immunodeficiency virus 1
  • Pyridones
  • Integrases