title: 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).
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.
authors: Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.|Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University , San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
authors: Je Ho
authors: JH
authors: Ryu
authors: Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.
authors: Jung A
authors: JA
authors: Lee
authors: Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.
authors: Shinae
authors: S
authors: Kim
authors: Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.
authors: Young Ah
authors: YA
authors: Shin
authors: Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University , San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
authors: Jewon
authors: J
authors: Yang
authors: Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.
authors: Hye Young
authors: HY
authors: Han
authors: Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.
authors: Hyun Joo
authors: HJ
authors: Son
authors: Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.
authors: Yong Hyuk
authors: YH
authors: Kim
authors: Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.
authors: Joon Ho
authors: JH
authors: Sa
authors: Life Science R&D Center, SK Chemicals , Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea.
authors: Jae-Sun
authors: JS
authors: Kim
authors: Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University , San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
authors: Jungeun
authors: J
authors: Lee
authors: Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University , San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
authors: Jeeyeon
authors: J
authors: Lee
authors: Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University , San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
authors: Hyeung-Geun
authors: HG
authors: Park
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; C000610579:SKI2852; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane