| Identification | Back Directory | [Name]
SKI-2852 | [CAS]
1346554-47-9 | [Synonyms]
SKI-2852
4-Pyrimidinecarboxamide, 2-[(2R)-4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1-piperazinyl]-N-[5-hydroxytricyclo[3.3.1.13,7]dec-2-yl]- | [Molecular Formula]
C27H34FN5O4S | [MOL File]
1346554-47-9.mol | [Molecular Weight]
543.65 |
| Hazard Information | Back Directory | [Description]
SKI2852 is a Highly Potent, Selective, and Orally Bioavailable Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) potentially for treatment of diabetics. SKI2852 bioactivity data: hHSD1 IC50 = 2.9nM; mHSD1 IC50 = 1.6nM; HEK293 IC50 = 4/4 nM; Mous PK: F = 96%; CYP3A4 IC50 > 10 μM; CYP2C19 IC50 > 10 μM. SKI2852 demonstrated no CYP and PXR liabilities, excellent PK profiles across species, and highly potent and sustainable PD activity. Repeated oral administration of SKI2852 significantly reduced blood glucose and HbA1c levels and improved the lipid profiles in ob/ob mice. | [Uses]
SKI2852 is a potent, selective and orally active 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor with IC50s of 1.6 nM and 2.9 nM against mHSD1 and hHSD1, respectively[1]. | [in vivo]
SKI2852 (20 mg/kg; oral; once daily for 25 days) significantly reduces blood glucose and HbA1c levels and improved the lipid profiles in ob/ob mice[1].
In Vivo PK Data for SKI2852[1]
| species | iva | pob | | CL (L/kg/h) | Vss (L/kg) | t1/2 (h) | AUC (μg × h/mL) | Cmax (μg/mL) | tmax (h) | AUC (μg × h/mL) | F (%) | | mousec | 0.42 | 1.1 | 1.7 | 2.35 | 2.21 | 1.0 | 11.26 | 96 | | ratc | 0.93 | 2.1 | 1.8 | 1.12 | 1.02 | 1.3 | 3.39 | 60 | | dogd | 0.36 | 2.4 | 4.7 | 1.47 | 1.12 | 2.1 | 11.52 | 98 |
a10% hydroxylpropyl-β-cyclodextrin was used as vehicle. b0.5% methylcellulose and 1% Tween80 was used as vehicle. cDosed iv at 1 mg/kg, po at 5mg/kg. dDosed iv at 0.5 mg/kg, po at 4 mg/kg.
| Animal Model: | ob/ob mice, diet-induced obesity (DIO) model[1] | | Dosage: | 20 mg/kg | | Administration: | Oral, once daily for 25 days | | Result: | Efficiently reduced postprandial glucose and/or blood HbA1c levels and suppressed hepatic mRNA levels of gluconeogenic enzymes. Clearly enhanced hepatic and whole-body insulin sensitivities in a hyperinsulinemic-euglycemic clamp experiment in DIO mice. |
| Animal Model: | C57BL/6 mice, rats and dogs[1] | | Dosage: | 0.5 or 4 mg/kg | | Administration: | IV or PO (Pharmacokinetic Analysis) | | Result: | Showed good pharmacokinetic profiles. |
| [References]
[1] Ryu JH, et al. 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 |
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