Abstract:
: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.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Li A,Yuan CC,Chow D,Chen M,Emery MG,Hale C,Zhang X,Subramanian R,St Jean DJ Jr,Komorowski R,Véniant M,Wang M,Fotsch Cdoi
10.1021/ml2001467subject
Has Abstractpub_date
2011-09-13 00:00:00pages
824-7issue
11issn
1948-5875journal_volume
2pub_type
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