N-Substituted Bicyclic Carbamoyl Pyridones: Integrase Strand Transfer Inhibitors that Potently Inhibit Drug-Resistant...

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• HIV-1 integrase (IN) is a key target for antiretroviral drugs.
• Cabotegravir (CAB), a second-generation integrase strand transfer inhibitor (INSTI), is used in long-acting HIV formulations.
• Missed doses of CAB can lead to low drug levels, potentially selecting for drug-resistant HIV-1 IN mutants and causing treatment failure.

Purpose of the Study:

• To develop simplified analogs of cabotegravir (CAB) with potent activity against wild-type and drug-resistant HIV-1 integrase.
• To identify novel compounds that can overcome resistance mechanisms associated with current INSTIs.

Main Methods:

• Synthesis of N-substituted bicyclic carbamoyl pyridones (BiCAPs) as simplified CAB analogs.
• Evaluation of inhibitory potencies against wild-type HIV-1 in single-round infection assays.
• Assessment of activity against HIV-1 constructs harboring clinically relevant IN resistance mutations.

Main Results:

• Several BiCAPs demonstrated potent inhibition of wild-type HIV-1.
• Lead compound 7c exhibited significantly higher potency than CAB against E138K/Q148K and G140S/Q148R double IN mutants.
• Multiple BiCAPs effectively inhibited the R263K IN mutant, a known challenge for second-generation INSTIs.

Conclusions:

• BiCAPs represent a promising class of novel HIV-1 integrase inhibitors.
• These compounds maintain high potency against key drug-resistant HIV-1 IN variants.
• BiCAPs offer potential therapeutic advantages for managing long-acting injectable HIV treatment and overcoming INSTI resistance.