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Purity: ≥98%
PF-915275 (PF915275) is a novel and selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11betaHSD1) with Ki of<1 nM and good pharmacokinetics. 11betaHSD1 play a key role in ligand-induced activation of the GR through the production of cortisol. Evidence from genetically modified mice suggests that inhibition of 11betaHSD1 might be a therapeutic approach to treat the metabolic syndrome. PF-915275 maintains potency in our cellular assay against human 11βHSD1 (HEK293, EC50 = 5 nM) and is selective against human 11βHSD2 (HEK293, 1.5% inhibition 10 μM). PF-915275 displays only weak affinity for the rodent choline transporter (Ki = 9.6 μM) and the hamster melatonin MT3 receptor (Ki = 9.6 μM) in the Cerep Bioprint screening panel. PF-915275 has good in vitro pharmacokinetic properties.
ln Vitro |
When coincubated with 300 nM enzyme substrate, PF-915275 is a potent inhibitor of 11βHSD1 (in vitro HEK293, EC50 of 15 nM) in this human 11βHSD1 overexpressed cell line. As expected from the species differences between humans and rodents found in biochemical assays, PF-915275 has an EC50 of 14,500 nM, making it a weak inhibitor of 11βHSD1 in rat FAO hepatoma cells. In primary hepatocytes from dogs, monkeys, and humans, PF-915275 exhibits species-dependent potency in blocking the cellular conversion of cortisone to cortisol. It also exhibits activity in human, monkey, and dog hepatocytes. At 10 μM, PF-915275 only exhibits 1.5% inhibition of 11βHSD2, suggesting a lack of significant inhibition. The impact of PF-915275, with an EC50 of 20 and 100 nM, respectively, on the conversion of cortisone to cortisol in primary human and monkey hepatocytes[1] is dose-dependent.
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ln Vivo |
Using cortisone and prednisone substrates, respectively, PF-915275 inhibits cortisone or prednisone turnover and produces EC50 values that are comparable to those in human hepatocytes in vivo 11βHSD1 activity (EC50 by PF-915275 is 18 and 13 nM, respectively). PF-915275 inhibits the conversion of prednisone to prednisolone mediated by 11βHSD1 in a dose-dependent manner. With a maximum tested dose of 3 mg/kg, an 87% inhibition is seen[1]. In monkeys, PF-915275 has a half-life of 22 hours [1]. After 8 hours of treatment, male cynomolgus monkeys given PF-915275 (0.1-3 mg/kg; oral administration; for 8 hours) show a trend in the dose-dependent reduction of fed plasma insulin. With PF-915275 treatment at 1 and 3 mg/kg, plasma insulin levels are significantly reduced (by 54 and 60%, respectively). Treatment has no effect on the levels of fat or plasma glucose[1].
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Animal Protocol |
Animal/Disease Models: Adult male cynomolgus monkeys (2-5 kg)[1]
Doses: 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg Route of Administration: Oral administration; for 8 hrs (hours) Experimental Results: There was a trend in dose-dependent lowering of fed plasma insulin after 8 h of dosing in these monkeys. Plasma insulin levels were Dramatically lowered (by 54 and 60%, respectively). |
References |
[1]. Bhat BG, et al. Demonstration of proof of mechanism and pharmacokinetics and pharmacodynamic relationship with 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), an inhibitor of 11 -hydroxysteroid dehydrogenase type 1, in cynomolg
[2]. Siu M, et al. N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3493-7. [3]. Courtney R, et al. Modulation of 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity biomarkers and pharmacokinetics of PF-00915275, a selective 11betaHSD1 inhibitor. J Clin Endocrinol Metab. 2008 Feb;93(2):550-6. |
Molecular Formula |
C18H14N4O2S
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Molecular Weight |
350.39
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CAS # |
857290-04-1
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Related CAS # |
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SMILES |
O=S(C1=CC=C(C2=CC=C(C#N)C=C2)C=C1)(NC3=NC(N)=CC=C3)=O
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Synonyms |
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (2.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.83 mg/mL (2.37 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.83 mg/mL (2.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.8540 mL | 14.2698 mL | 28.5396 mL | |
5 mM | 0.5708 mL | 2.8540 mL | 5.7079 mL | |
10 mM | 0.2854 mL | 1.4270 mL | 2.8540 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.