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.

Designing Out PXR Activity on Drug Discovery Projects: A Review of Structure-Based Methods, Empirical and Computational Approaches

“…This liability was completely negated by the addition of a fluorine atom and a nitrogen atom, resulting in the pyrimidine derivative 235 (SKI2852), Figure 64, which was selected as a development candidate. 233 Unfortunately, no further data is given for the individual changes, so it is impossible to ascertain the impact of each change. However, this again highlights the worthiness of simple molecular changes, including the importance a fluorine atom can make.…”

“…A more recent example on the same target comes from the Life Science R &D Centre at SK Chemicals in Korea who found their series, exemplified by 234 , Figure , to activate PXR. This liability was completely negated by the addition of a fluorine atom and a nitrogen atom, resulting in the pyrimidine derivative 235 (SKI2852), Figure , which was selected as a development candidate . Unfortunately, no further data is given for the individual changes, so it is impossible to ascertain the impact of each change.…”

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

“…These and other preclinical findings build a strong case that inhibition of 11β-HSD1 may be an efficacious approach for the treatment of metabolic syndrome. As a result, much attention has been focused on the discovery and development of inhibitors of this enzyme. − In clinical trials, Incyte, Merck, and others have demonstrated that 11β-HSD1 inhibitors improved glycaemic control, lipid profiles, and blood pressure with modest weight loss . In addition to this indication, we recently explored and proposed atheroprotection as an emerging indication for this target.…”

Inhibition of 11β-hydroxysteroid dehydrogenase 1 relieves fibrosis through depolarizing of hepatic stellate cell in NASH

“…In this study, we applied 3D cultures in drug discovery and repositioning to find valuable targets and drugs for efficient anti-fibrotic therapy. Our previous work suggested that J2H-1702, a novel inhibitor of 11βHSD1, has great potential as a novel candidate drug for treating diabetes and metabolic diseases, with pharmacokinetic and safety profiles [ 15 , 16 ]. In Phase I clinical trial, J2H-1702 was shown to be well-tolerated with mild adverse events after oral administration in healthy male subjects, not requiring any intervention or treatments.…”

“…Although 11βHSD1 contributes to liver fibrosis via increasing active glucocorticoid, its role in liver fibrosis is still controversial [ 12 – 14 ]. In a previous study, we developed pyridineamide derivatives (J2H-1702, 2-((R)-4-(2-Fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1 R,2 s,3 S,5 S,7 S)-5- hydroxyadamantan-2-yl) pyrimidine-4-carboxamide) as 11βHSD1 inhibitors to treat diabetes and metabolic disease and found that J2H-1702 sufficiently inhibited hepatic gluconeogenesis and partial improved lipid profiles and metabolic parameters [ 15 , 16 ].…”