- 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 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)
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A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11β-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.
- Ryu, Je Ho,Lee, Jung A,Kim, Shinae,Shin, Young Ah,Yang, Jewon,Han, Hye Young,Son, Hyun Joo,Kim, Yong Hyuk,Sa, Joon Ho,Kim, Jae-Sun,Lee, Jungeun,Lee, Jeeyeon,Park, Hyeung-Geun
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- PICOLINAMIDE AND PYRIMIDINE-4-CARBOXAMIDE COMPOUNDS, PROCESS FOR PREPARING AND PHAMACEUTICAL COMPOSITION COMPRISING THE SAME
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Provided are picolinamide and pyrimidine-4-carboxamide compounds, a method for preparing the same, a pharmaceutical composition containing the same, and a medical use using the compound as an agent for preventing, regulating, and treating diseases related to regulation of glucocorticoids by using selective inhibitory activity of the compound for an 11β-HSD1 enzyme. The picolinamide and pyrimidine-4-carboxamide compounds of the present invention are selective inhibitors of human-derived 11β-HSD1 enzymes, and are useful in an agent for preventing, regulating, and treating diseases related to glucocorticoid regulation in which human- derived 11β-HSD1 enzymes are involved, for example, metabolic syndromes such as, type 1 and type 2 diabetes, diabetes later complications, latent autoimmune diabetes adult (LAD A), insulin tolerance syndromes, obesity, impaired glucose tolerane (IGT), impaired fasting glucose (IFG), damaged glucose tolerance, dyslipidemia, atherosclerosis, hypertension, etc.
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Page/Page column 95-96
(2011/11/30)
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