AZD8329
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 89nM and 15nM, 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.
Mechanism of Action
11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor
Original Therapeutic Area
Metabolic
CNS Penetrant
Low
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Scott JS., et al. (2012).
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). J Med Chem. 2012 Nov 26;55(22):10136-47. doi: 10.1021/jm301252n. Epub 2012 Nov 7. PMID: 23088558.
