Discovery of 2-((R)-4-(2-Fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-( (1R,2s,3S,5S,7S)-5-hydroxyadamantan-2-y1)pyrimidine-4-carboxamide (SKI2852): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of 11 beta-Hydroxysteroid Dehydrogenase Type 1 (11 beta-HSD1)

作者：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^*

来源：Journal of Medicinal Chemistry, 2016, 59(22): 10176-10189.

DOI：10.1021/acs.jmedchem.6b01122

A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11 beta-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.

• 出版日期2016-11-24