Species-Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with In Vivo Antialphaviral Activity DOI Creative Commons
Mohammad Anwar Hossain,

A. Mayo,

Anirban Ghoshal

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: May 12, 2025

RA-0002034 (1) is a potent covalent inhibitor targeting the nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of 1 were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione S-transferase (GST)-catalyzed conjugation. This metabolic liability contrasted with slower observed human hepatocytes preclinical species, such as rats, dogs, monkeys. Cross-species studies confirmed dominance GST-driven whereas oxidative pathways more pronounced dogs. Despite systemic clearance, achieved antiviral efficacy reducing chikungunya (CHIKV) viral loads multiple tissues. These cross-species pharmacokinetic support continued evaluation potential antialphaviral further define contribution hepatic non-hepatic GST humans.

Language: Английский

Species-Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with In Vivo Antialphaviral Activity DOI Creative Commons
Mohammad Anwar Hossain,

A. Mayo,

Anirban Ghoshal

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: May 12, 2025

RA-0002034 (1) is a potent covalent inhibitor targeting the nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of 1 were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione S-transferase (GST)-catalyzed conjugation. This metabolic liability contrasted with slower observed human hepatocytes preclinical species, such as rats, dogs, monkeys. Cross-species studies confirmed dominance GST-driven whereas oxidative pathways more pronounced dogs. Despite systemic clearance, achieved antiviral efficacy reducing chikungunya (CHIKV) viral loads multiple tissues. These cross-species pharmacokinetic support continued evaluation potential antialphaviral further define contribution hepatic non-hepatic GST humans.

Language: Английский

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