Metabolism and disposition of a potent and selective JNK inhibitor [14C]tanzisertib following oral administration to rats, dogs and humans

Abstract1. The disposition of tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, orally active c-Jun amino-terminal kinase inhibitor intended for treatment of fibrotic diseases was studied in rats, dogs and humans following a single oral dose of [14C]tanzisertib (Independent Investigational Review Board Inc., Plantation, FL).2. Administered dose was quantitatively recovered in all species and feces/bile was the major route of elimination. Tanzisertib was rapidly absorbed (Tmax: 1–2 h) across all species with unchanged tanzisertib representing >83% of plasma radioactivity in dogs and humans, whereas <34% was observed in rats. Variable amounts of unchanged tanzisertib (1.5–32% of dose) was recovered in urine/feces across all species, the highest in human feces.3. Metabolic profiling revealed that tanzisertib was primarily metabolized via oxidation and conjugation pathways, but extensively metabolized in rats relative to dogs/humans...