Carbene reactive metabolite explains the hepatotoxicity of the hot flashes drug fezolinetant: A DFT investigation
Abstract
Fezolinetant, the first-in-class hot flashes drug, was flagged in September 2024 by US-FDA for liver injury. It is alarming that an FDA-approved drug shows liver toxicity within a year. Fezolinetant's metabolic pathways and metabolites are not disclosed in the FDA label, clinical trial, or other literature reports. This creates a gap in understanding the mechanisms of metabolism and toxicity. In this manuscript, we have investigated novel metabolic pathways that generate reactive metabolites and rationalize hepatotoxicity. Quantum chemical calculations were performed to assess the reactivity of various sites using B3LYP/CC-PVTZ level of theory and H2O2 as the model oxidant. A combination of reaction free-energy (ΔG°) ≤ kBT = 18.5 kcal/mol and docking-based site of metabolism (SOM) to Heme-Fe distance (DAFe ≤ 6 ± 1.95 Å) criterion was used to assess metabolism feasibilities. Metabolic reactions and sites were considered potential only if both reactivity and accessibility criteria were met. A novel pathway involving Me oxidation at the thiadiazole ring to acid leading to reactive Fezo-carbene metabolite is most feasible (ΔG° and DAFe: 11 kcal/mol and 6.84 Å). Other feasible pathways include radical formation at the triazolopiperazine ring forming the Fezo-pip-dehydro metabolite (12 kcal/mol and 7.96 Å). The epoxidation, N-oxidation, and S-oxidation of the fluorophenyl, triazolopiperazine, and thiadiazole ring cleavage have minor contributions. Global and local electrophilicity…
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