AZD 4017

AZD 4017 is a potent, selective 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) inhibitor, with an IC₅₀ of 7 nM. IC50 & Target: IC50: 7 nM (11β-HSD1)^[1]. In Vitro: AZD 4017 displays excellent selectivity versus the related enzymes 11-βHSD2, 17β-HSD1, 17β-HSD3 (all IC₅₀>30 μM) and shows no measurable activity against the glucocorticoid and mineralocorticoid receptors. Despite having high potency for the human form of 11β-HSD1, AZD 4017 shows much reduced activity across species with the exception of cynomolgous monkey (IC₅₀=0.029 μM). Additionally, as it is believed that adipose is a key target organ, inhibition of 11β-HSD1 activity is measured in isolated human adipocytes from nondiabetic volunteers. AZD 4017 is shown to be a potent inhibitor in this key target tissue (IC₅₀=0.002 μM) in good agreement with the enzyme potency, thus providing some confidence that AZD 4017 is not restricted from adipose tissue by the fact that it was acidic^[1]. In Vivo: Since AZD 4017 has lower potency against the mouse enzyme, only a limited number of preclinical pharmacodynamic measurements are performed. Increasing the dose further led to a maximal effect of approximately 70% inhibition at 1500 mg/kg, equivalent to 10×IC₅₀ in the mouse, demonstrating the dose dependent inhibition of 11β-HSD1 by AZD 4017 in this model^[1].