2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2016 Nov 23;59(22):10176-10189. doi: 10.1021/acs.jmedchem.6b01122.
Je Ho Ryu 1 2,  Jung A Lee 1,  Shinae Kim 1,  Young Ah Shin 1,  Jewon Yang 2,  Hye Young Han 1,  Hyun Joo Son 1,  Yong Hyuk Kim 1,  Joon Ho Sa 1,  Jae-Sun Kim 1,  Jungeun Lee 2,  Jeeyeon Lee 2,  Hyeung-Geun Park 2
Affiliations

Affiliations

  • 1 Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.
  • 2 Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University , San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
PMID: 27798827 DOI: 10.1021/acs.jmedchem.6b01122
Abstract

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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