Potent Long-Acting Inhibitors Targeting the HIV-1 Capsid Based on a Versatile Quinazolin-4-one Scaffold.

Area of Science:

• Medicinal Chemistry
• Virology
• Pharmacology

Background:

• Long-acting (LA) antiretroviral therapy for human immunodeficiency virus-1 (HIV-1) offers advantages over daily oral regimens.
• Developing LA HIV-1 therapies requires compounds with exceptional potency, low clearance, and high stability.
• Stringent criteria exist for drug candidates, including minimal side effects and drug-drug interactions.

Purpose of the Study:

• To report the discovery of novel quinazolinone-based capsid inhibitors for potential LA HIV-1 therapy.
• To characterize the structural modifications, potency, and synthetic accessibility of these compounds.
• To present detailed data for a prototypical compound, GSK878.

Main Methods:

• Synthesis and structural modification of quinazolinone-based compounds.
• In vitro assessment of antiviral potency against HIV-1.
• X-ray co-crystal structure determination.
• Pharmacokinetic studies (subcutaneous and intramuscular) in rats and dogs.

Main Results:

• Quinazolinone core allows extensive structural modification while maintaining picomolar HIV-1 potency.
• Compounds are efficiently assembled via multi-component reactions and can be isolated in stereochemically pure forms.
• Prototypical compound GSK878 exhibits favorable characteristics, including detailed structural and pharmacokinetic data.

Conclusions:

• Novel quinazolinone capsid inhibitors represent a promising scaffold for developing LA HIV-1 antiretroviral therapy.
• These compounds meet key criteria for LA therapy development, including high potency and synthetic tractability.
• GSK878's characterization supports its potential as a candidate for further development in HIV-1 treatment strategies.