| Identification | Back Directory | [Name]
(5S)-2-[(1S,2S,4R)-Bicyclo[2.2.1]hept-2-ylamino]-5-methyl-5-(1-methylethyl)-4(5H)-thiazolone | [CAS]
1095565-81-3 | [Synonyms]
AMG-221
(5S)-2-[(1S,2S,4R)-Bicyclo[2.2.1]hept-2-ylamino]-5-methyl-5-(1-methylethyl)-4(5H)-thiazolone | [Molecular Formula]
C14H22N2OS | [MDL Number]
MFCD18206790 | [MOL File]
1095565-81-3.mol | [Molecular Weight]
266 |
| Hazard Information | Back Directory | [Uses]
AMG-221 is an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with a Ki 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 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].
| Animal Model: | Diet-Induced Obesity (DIO) Mice[2] | | Dosage: | 25 or 50 mg/kg (prepare in 0.1% Tween-80 and 0.5% CMC in water) | | Administration: | Orally gavaged; twice a day for 13 or 14 days | | Result: | There were statistically significant decreases in insulin levels in all treated groups when compared with the vehicle control group on day 13.
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| [References]
[1] Seb Caille,?et al. Two asymmetric syntheses of AMG 221, an inhibitor of 11beta-hydroxysteroid dehydrogenase type 1.J Org Chem.?2009 May 15;74(10):3833-42. DOI:10.1021/jo900287b
[2] Murielle M Véniant,?et al. Discovery of a potent, orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for clinical study: identification of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). J Med Chem.?2010 Jun 10;53(11):4481-7. DOI:10.1021/jm100242d
[3] Aiwen Li,?et al. Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes. ACS Med Chem Lett.?2011 Sep 13;2(11):824-7. DOI:10.1021/ml2001467 |
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