Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes

Area of Science:

• Biochemistry
• Pharmacology
• Virology

Background:

• PF74 and 11L are potent modulators of the HIV-1 capsid protein, impacting early and late stages of the viral life cycle.
• These compounds exhibit high clearance rates in human liver microsomes (HLMs), necessitating a deeper understanding of their metabolism.

Purpose of the Study:

• To elucidate the phase-I metabolism of PF74 and 11L in HLMs.
• To identify key metabolic pathways and soft spots for structural optimization of these HIV-1 capsid modulators.

Main Methods:

• In vitro incubation of PF74 and 11L with HLMs.
• Analysis of phase-I metabolites using ultra-performance liquid chromatography-ultraviolet-high-resolution mass spectrometry (UPLC-UV-HRMS).

Main Results:

• 17 phase-I metabolites of PF74 and 16 phase-I metabolites of 11L were putatively identified.
• Major metabolic pathways for PF74 included oxidation and demethylation; for 11L, they included oxidation, demethylation, dehydrogenation, and oxidative deamination.
• Key metabolic soft spots were identified in the indole ring and N-methyl group of PF74, and the aniline group, benzene ring, N-methyl, and methoxy group of 11L.

Conclusions:

• The study identified major metabolites and metabolic pathways for PF74 and 11L in HLMs.
• Understanding these metabolic liabilities provides crucial guidance for the rational structural optimization of novel HIV-1 capsid modulators.
• This research contributes to the development of more effective HIV-1 therapeutic agents.