Abstract

6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine (BIIB021), a synthetic HSP90 inhibitor, exhibited promising antitumor activity in preclinical models and was in development for the treatment of breast cancer. The metabolism and excretion of BIIB021 was investigated in rats and dogs after oral administration of [¹⁴C]BIIB021. The administered radioactive dose was quantitatively recovered in both species, and feces/bile was the major route of excretion. Metabolic profiling revealed that BIIB021 is extensively metabolized primarily via hydroxylation of the methyl group (M7), O-demethylation (M2), and to a lesser extent by glutathione conjugation (M8 and M9). M7 was further metabolized to form the carboxylic acid (M3) and glucuronide conjugate (M4). Human plasma obtained from the phase I study in cancer patients were also analyzed to assess the metabolism of BIIB021 in humans and to ensure that selected animal species were exposed to all human major metabolites. Results suggested that BIIB021 is metabolized via hydroxylation followed by carboxylation and glucuronidation in humans consistent with rat and dog; however, an additional dominant circulating metabolite, hydroxylation at the purine ring (M10), was identified in humans. Preliminary in vitro studies using liver cytosolic fractions indicated that M10 formation is primarily catalyzed by aldehyde oxidase (AO). AO catalytic activity for M10 formation was the highest in the monkey, followed by mouse, human, and rat. The apparent K_m and V_max values of M10 formation were 174 ± 8 µM and 14.0 ± 0.3 pmol•min⁻¹•mg protein⁻¹ in human and 132 ± 9 µM and 131 ± 4 pmol•min⁻¹•mg protein⁻¹ in monkey, respectively.