Mechanism of action: 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor

Preclinical pharmacology

AZD8329 is a potent inhibitor of human recombinant 11β-HSD1 (IC50 9 nM) and of 11β-HSD1 in isolated human adipocytes (IC50 2 nM) in vitro.  AZD8329 is selective (> 5000x) for 11β-HSD1 over human recombinant 11β-HSD2 and the closely homologous enzymes 17β-HSD1 and 17β-HSD3 in vitro.

AZD8329 is an inhibitor of rat and dog recombinant 11β-HSD1 with IC50 values of 89 and 15 nM, respectively.  AZD8329 significantly reduced 11β-HSD1 activity in adipose tissue and liver samples, when tissue 11β-HSD1 activity was assayed ex vivo, following a single oral dose of 10 mg/kg to Han Wistar rats (compound plasma levels of ~5x IC50).  In diet-induced obese mice, another rodent-active AZ 11β-HSD1 inhibitor induced significant, and approximately half-maximal, reduction in adipose mass and weight gain when unbound compound exposure was equivalent to the in vitro IC50 concentration at trough.

CNS penetration is likely low.

Additional Information

Clinical trials for this compound

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Publications for this compound

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ACS Publications

Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4-[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)

Gene information from the NCBi

This compound works on the following genes: