7 research outputs found
Discovery of Clinical Candidate 2‑((2<i>S</i>,6<i>S</i>)‑2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor
BMS-816336
(<b>6n-2</b>), a hydroxy-substituted adamantyl
acetamide, has been identified as a novel, potent inhibitor against
human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
enzyme (IC<sub>50</sub> 3.0 nM) with >10000-fold selectivity over
human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). <b>6n-2</b> exhibits a robust acute pharmacodynamic effect in cynomolgus
monkeys (ED<sub>50</sub> 0.12 mg/kg) and in DIO mice. It is orally
bioavailable (%<i>F</i> 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. <b>6n-2</b> 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