| Autor: |
David Chow, David J. St. Jean, Michelle Chen, Murielle M. Véniant, Xiping Zhang, Minghan Wang, Maurice Emery, Chester Chenguang Yuan, Renee Komorowski, Clarence Hale, Aiwen Li, Raju Subramanian, Christopher H. Fotsch |
| Rok vydání: |
2011 |
| Předmět: |
|
| Zdroj: |
ACS Medicinal Chemistry Letters. 2:824-827 |
| ISSN: |
1948-5875 |
| Popis: |
All eight of the major active metabolites of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221, compound 1), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 that has entered the clinic for the treatment of type 2 diabetes, were synthetically prepared and confirmed by comparison with samples generated in liver microsomes. After further profiling, we determined that metabolite 2 was equipotent to 1 on human 11β-HSD1 and had lower in vivo clearance and higher bioavailability in rat and mouse. Compound 2 was advanced into a pharmacodynamic model in mouse where it inhibited adipose 11β-HSD1 activity. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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