Discovery of 2-((R)-4-(2-Fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1R,2s,3S,5S,7S)-5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide (SKI2852): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of 11ß-Hydroxysteroid Dehydrogenase Type 1 (11ß-HSD1).
J Med Chem
; 59(22): 10176-10189, 2016 11 23.
Article
in En
| MEDLINE
| ID: mdl-27798827
ABSTRACT
A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 was synthesized and evaluated to optimize the lead compound 9. The combination of the replacement of a pyridine ring of 9 with a pyrimidine ring and the introduction of an additional fluorine substituent at the 2-position of the phenyl ring resulted in the discovery of a potent, selective, and orally bioavailable inhibitor, 18a (SKI2852), which demonstrated no CYP and PXR liabilities, excellent PK profiles across species, and highly potent and sustainable PD activity. Repeated oral administration of 18a significantly reduced blood glucose and HbA1c levels and improved the lipid profiles in ob/ob mice. Moreover, the HbA1c-lowering effect of metformin was synergistically enhanced in combination with 18a.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidines
/
Adamantane
/
11-beta-Hydroxysteroid Dehydrogenase Type 1
/
Enzyme Inhibitors
/
Drug Discovery
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2016
Document type:
Article