Discovery and Preclinical Profiling of GSK3839919, a Potent HIV-1 Allosteric Integrase Inhibitor

Area of Science:

• Medicinal Chemistry
• Virology
• Pharmacology

Background:

• Allosteric HIV-1 integrase inhibitors (ALLINIs) are a novel class of antiretroviral agents.
• Previous research focused on modifying the C5 moiety of pyridinyl ALLINIs, leading to compound 12.

Purpose of the Study:

• To develop an improved ALLINI with reduced toxicity.
• To characterize the virology, pharmacokinetic, and toxicology profiles of GSK3839919 (22).

Main Methods:

• Structure-activity relationship studies and chemical synthesis.
• In vitro enzyme inhibition assays and cell-based antiviral assays.
• Preclinical pharmacokinetic and toxicology studies in animal models.

Main Results:

• Compound 12 demonstrated potent HIV-1 integrase inhibition but caused lipid hepatocellular vacuolation in rats.
• GSK3839919 (22), a C6-demethylated analog, showed reduced lipid vacuolation in vitro and in vivo.
• Compound 22 maintained single-digit nanomolar potency and favorable pharmacokinetic properties.

Conclusions:

• GSK3839919 (22) represents a promising advancement in ALLINI development.
• The C6-demethylation strategy effectively mitigated a key toxicity finding.
• Compound 22 warrants further investigation as a potential HIV-1 therapeutic.