In‐vitro metabolism studies with BLX‐1026, a novel Orexin‐2 agonist with anti‐obesity activity

BLX‐1026 is a water soluble, amino‐acid conjugated small molecule with in vitro Orexin‐2 receptor agonist activity. Orexin receptors have been implicated in non‐exercise activity thermogenesis. Increased levels of Orexin‐2 receptors have been observed in obesity‐resistant rats and decreased Orexin‐A levels observed in obese humans. Phase I metabolism studies have been conducted with BLX‐1026 in rat, mice, dog, monkey and human liver microsomes and human liver S9 fractions. It is found to be stable in all five species liver microsomes but shows a 61% degradation in the human S9 fractions when incubated for 1 hour. When orally administered to dogs and rats, it is found to have one major metabolite. Upon oral administration to rats and analysis of bile, it converts into the same major metabolite and three minor metabolites of which one is observed to be a glucuronide conjugate indicating Phase II metabolism. Further in vitro studies are underway with BLX‐1026 to further characterize its metabolic pathway.