BMS-816336

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS‐816336 as an inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon‐14 labeled material was required for use in metabolic profiling. [Phenyl‐14C(U)]BMS‐816336 was synthesized in 8 steps and 22% radiochemical yield from commercially available [14C(U)]bromobenzene. The radiochemical purity of [phenyl‐14C(U)]BMS‐816336 was 100% having a specific activity of 84.4 μCi/mg or 28.8 mCi/mmol for a total of 8.9 mCi. It was also necessary to synthesize [13C6]BMS‐816336 for use as a liquid chromatography/mass spectrometry standard. [13C6]BMS‐816336 was also prepared in 8 labeled steps in 26% yield from [13C6]bromobenzene.

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC₅₀ 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED₅₀ 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11β-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.