AMG-221

AMG-221 is an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with a K_i of 12.8 nM in vitro biochemical scintillation proximity assay (SPA) and an IC₅₀ of 10.1 nM in cell-based assays^[1][2]. AMG-221 can be used for the research of type 2 diabetes^[3]. In Vitro: AMG-221 shows selectivity over 11β-HSD2, 17β-HSD1, and glucocorticoid receptor (GR) (IC₅₀ values for all assays are >10 μM)^[2]. In Vivo: AMG-221 (25 or 50 mg/kg; b.i.d.; orally gavaged) inhibits 11β-HSD1 activity in DIO mice. At the end of the study, fed blood glucose shows statistically significant reduction in comparison to the vehicle group. On day 14 and after a 12 h fast, glucose tolerance is slightly improved in the AMG-221 treatment groups compared with the vehicle group^[2].
11β-HSD1 activity is inhibited by 33%, 55%, and 47% in the inguinal fat at 4 h after AMG-221 is orally gavaged at 5, 15, and 50 mg/kg, respectively. At 8 h, the 11β-HSD1 activity in the inguinal fat of the 5 mg/kg group has returned to a level (～10% inhibition) close to that in the control animals treated with vehicle, but there is still significant inhibition in the 15 and 50 mg/kg groups (36% and 39% inhibition, respectively)^[2].
AMG-221 has a good bioavailability in mouse, rat, and dog. However, the bioavailability in monkey is low^[2].
AMG-221 exhibits moderate oral bioavailability (male CD1 mouse 31%) following oral administration (10 mg/kg)^[3].
AMG-221 exhibits terminal elimination half-life (male CD1 mouse 3.32 h) due to high plasma clearance (3.31 L/h/kg) combined with large volumes of distribution (0.9 L/kg) following intravenous administration (2 mg/kg)^[3].