| Identification | Back Directory | [Name]
N-(6-Amino-2-pyridinyl)-4'-cyano-[1,1'-biphenyl]-4-sulfonamide | [CAS]
857290-04-1 | [Synonyms]
PF 915275
PF 915275;PF915275
N-(6-aminopyridin-2-yl)-4-(4-cyanophenyl)benzenesulfonamide
N-(6-Amino-2-pyridinyl)-4'-cyano-[1,1'-biphenyl]-4-sulfonamide
[1,1'-Biphenyl]-4-sulfonamide, N-(6-amino-2-pyridinyl)-4'-cyano- | [Molecular Formula]
C18H14N4O2S | [MDL Number]
MFCD12828758 | [MOL File]
857290-04-1.mol | [Molecular Weight]
350.39 |
| Chemical Properties | Back Directory | [Boiling point ]
610.9±65.0 °C(Predicted) | [density ]
1.44±0.1 g/cm3(Predicted) | [storage temp. ]
Store at RT | [solubility ]
Soluble in DMSO | [form ]
Powder | [pka]
7.97±0.29(Predicted) | [color ]
White to pink | [InChI]
InChI=1S/C18H14N4O2S/c19-12-13-4-6-14(7-5-13)15-8-10-16(11-9-15)25(23,24)22-18-3-1-2-17(20)21-18/h1-11H,(H3,20,21,22) | [InChIKey]
ZESFDAKNYJQYKO-UHFFFAOYSA-N | [SMILES]
C1(C2=CC=C(C#N)C=C2)=CC=C(S(NC2=NC(N)=CC=C2)(=O)=O)C=C1 |
| Hazard Information | Back Directory | [Uses]
PF-915275 is a potent, selective and orally active human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) inhibitor with a Ki of 2.3 nM and an EC50 of 15 nM (in HEK293 cells). The dose-dependent effect of PF-915275 on conversion of cortisone to cortisol in primary human and monkey hepatocytes, with an EC50 of 20 and 100 nM, respectively[1][2][3]. | [Biological Activity]
PF-915275 is an orally activepotent and selective 11beta-hydroxysteroid dehydrogenase type 1 (11?-HSD1HSD11B1) inhibitor (human 11?-HSD1 Ki <1 nM; cellular IC50 = 5 nM using human 11?-HSD1-transfected HEK293) with reduced potency toward non-human species (human/monkey/dog hepatocytes EC50 = 20/100/120 nM; mouse 11?-HSD1 Ki = 750 nMr at hepatoma EC50 = 14 μM). PF-915275 (0.1-3-mg/kg via nasogastric intubations) inhibits prednisone-to-prednisolone conversion in cynomolgus monkeys (by 87% with 3 mg/kg) in vivo and reduces plasma insulin increase following prednisone & resumed feeding (4 hrs post PF-915275) among overnight fasted monkeys. | [in vivo]
The inhibition of either cortisone or prednisone turnover with PF-915275 yields similar EC50 values to that in human hepatocytes (EC50 by PF-915275 is 18 and 13 nM using cortisone and prednisone substrates, respectively) in vivo 11βHSD1 activity[1].
PF-915275 dose-dependently inhibits 11βHSD1-mediated conversion of prednisone to prednisolone. A maximum of 87% inhibition is observed, with the highest tested dose of 3 mg/kg[1].
The half-life of PF-915275 is 22 hours in monkey[1].
PF-915275 (0.1-3 mg/kg; oral administration; for 8 hours; male cynomolgus monkeys) treatment shows a trend in dose-dependent lowering of fed plasma insulin after 8 h of dosing in these monkeys. Plasma insulin levels are significantly lowered (by 54 and 60%, respectively) at 1 and 3 mg/kg PF-915275 treatment. Plasma glucose or lipid levels are not altered with treatment[1]. | Animal Model: | Adult male cynomolgus monkeys (2-5 kg)[1] | | Dosage: | 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg | | Administration: | Oral administration; for 8 hours | | Result: | There was a trend in dose-dependent lowering of fed plasma insulin after 8 h of dosing in these monkeys. Plasma insulin levels were significantly lowered (by 54 and 60%, respectively).
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| [storage]
Store at RT | [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 cynomolgus monkeys. J Pharmacol Exp Ther. 2008 Jan;324(1):299-305. DOI:10.1124/jpet.107.128280
[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. DOI:10.1016/j.bmcl.2009.05.011
[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. DOI:10.1210/jc.2007-1912 |
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Musechem
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www.musechem.com |
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