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Purity: ≥98%
PF-06869206 (PF06869206) is a novel, potent, selective and orally bioavailable inhibitor of the sodium-phosphate cotransporter NaPi2a (SLC34A1) with the potential to treat CKD. It inhibits SLC34A1 with an IC50 of 380 nM. Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary phosphate excretion and correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease-mineral and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. The oral PK profile of inhibitor PF-06869206 in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.
| ln Vitro |
PF-06869206 has a good combination of isoform selectivity, 380 nM NaPi2a inhibitory activity, and acceptable water solubility (46 μM). PF-06869206 was tested for efficacy using rodent NaPi2a and NaPi2c cell lines. Comparable submicromolar activity of PF-06869206 has been seen against human, rat, and mouse NaPi2a isoforms; the IC50 values for rat and mouse NaPi2a are 0.4±0.047 μM and 0.54±0.099 μM, respectively [1].
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| ln Vivo |
To ascertain whether PF-06869206 is suitable for in vivo pharmacological research, mouse PK tests were conducted. Rat and mouse clearance was found to be modest. In rats, oral bioavailability of 5 mg/kg was good; in mice, it was moderate. Both species showed a disproportionate increase in exposure at the higher oral dose of 50 mg/kg, suggesting saturation of removal. When administered intravenously (10 mg/kg), PF-06869206 has an intermediate terminal elimination half-life (t1/2=1.35 hours, 0.75 hours) in both C57BL6 mice and Wistar-Han rats (10 mg/kg). Furthermore, rat liver microsomes (RLM) have high permeability (14×10-6 cm/s) and a low clearance rate (<14 μL/min/mg; HLM=39 μL/min/mg) [1].
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| References |
[1]. Filipski KJ, et al. Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1). ACS Med Chem Lett. 2018 Apr 12;9(5):440-445
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| Molecular Formula |
C15H14CLF3N4O2
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|---|---|
| Molecular Weight |
374.745472431183
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| CAS # |
2227425-05-8
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| SMILES |
N#CC1=C(C(F)(F)F)N=C2C(NC(C)=C2Cl)=C1N3C[C@@H](CO)OCC3
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| InChi Key |
ATFQBBCQZKVZJN-QMMMGPOBSA-N
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| InChi Code |
InChI=1S/C15H14ClF3N4O2/c1-7-10(16)11-12(21-7)13(23-2-3-25-8(5-23)6-24)9(4-20)14(22-11)15(17,18)19/h8,21,24H,2-3,5-6H2,1H3/t8-/m0/s1
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| Chemical Name |
(S)-3-chloro-7-(2-(hydroxymethyl)morpholino)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile
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| Synonyms |
PF06869206; PF 06869206; PF-06869206
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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) |
DMSO : ~100 mg/mL (~266.84 mM)
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6684 mL | 13.3422 mL | 26.6845 mL | |
| 5 mM | 0.5337 mL | 2.6684 mL | 5.3369 mL | |
| 10 mM | 0.2668 mL | 1.3342 mL | 2.6684 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.
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