Journal of Medicinal Chemistry p. 10176 - 10189 (2016)
Update date:2022-08-15
Topics:
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
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.
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