Synonym
PF-06869206; PF 06869206; PF06869206;
IUPAC/Chemical Name
(S)-3-chloro-7-(2-(hydroxymethyl)morpholino)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile
InChi Key
ATFQBBCQZKVZJN-QMMMGPOBSA-N
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
SMILES Code
N#CC1=C(C(F)(F)F)N=C2C(NC(C)=C2Cl)=C1N3C[C@@H](CO)OCC3
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solutecarrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerularfiltered 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).
Biological target:
PF-06869206 is an orally bioavailable selective inhibitor of the sodium-phosphate cotransporter NaPi2a (SLC34A1) with an IC50 of 380 nM.
In vitro activity:
PF-06869206 elicited in these cells a statistically significant, concentration-dependent reduction of 32P uptake (Figure 1). The highest dose of PF-06869206 (30 μM) resulted in a reduction in radioactivity to 46.2% ± 1.5% of control levels, compared with a reduction to 92.6% ± 2.1% of control radioactivity at the lowest dose of PF-06869206 (30 nM) and a reduction to 30.5% ± 2.9% of control with 5 mM phosphonoformic acid (PFA), a nonselective inhibitor of sodium-phosphate transporters that was used as a positive control (Figure 1).
Reference: J Clin Invest. 2020 Dec 1;130(12):6510-6522. https://pubmed.ncbi.nlm.nih.gov/32853180/
In vivo activity:
The authors assessed the effects of the first orally bioavailable Npt2a inhibitor (Npt2a-I) PF-06869206 in normal mice and mice that had undergone subtotal nephrectomy (5/6 Nx), a mouse model of CKD. In normal mice, Npt2a inhibition caused a dose-dependent increase in urinary phosphate (ED50 approximately 21 mg/kg), calcium, sodium and chloride excretion. In contrast, urinary potassium excretion, flow rate and urinary pH were not affected dose dependently. Plasma phosphate and PTH significantly decreased after 3 hours, with both returning to near baseline levels after 24 hours. Similar effects were observed in the mouse model of CKD but were reduced in magnitude.
Reference: J Am Soc Nephrol. 2019 Nov;30(11):2128-2139. https://pubmed.ncbi.nlm.nih.gov/31409727/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMF |
1.0 |
2.67 |
|
| DMSO |
58.7 |
156.55 |
|
| Ethanol |
23.0 |
61.37 |
|
| Ethanol:PBS (pH 7.2) (1:3) |
0.3 |
0.67 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
374.75
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Clerin V, Saito H, Filipski KJ, Nguyen AH, Garren J, Kisucka J, Reyes M, Jüppner H. Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion. J Clin Invest. 2020 Dec 1;130(12):6510-6522. doi: 10.1172/JCI135665. PMID: 32853180; PMCID: PMC7685737.
2. Thomas L, Xue J, Tomilin VN, Pochynyuk OM, Dominguez Rieg JA, Rieg T. PF-06869206 is a selective inhibitor of renal Pi transport: evidence from in vitro and in vivo studies. Am J Physiol Renal Physiol. 2020 Sep 1;319(3):F541-F551. doi: 10.1152/ajprenal.00146.2020. Epub 2020 Aug 3. PMID: 32744087; PMCID: PMC7509280.
3. Thomas L, Xue J, Murali SK, Fenton RA, Dominguez Rieg JA, Rieg T. Pharmacological Npt2a Inhibition Causes Phosphaturia and Reduces Plasma Phosphate in Mice with Normal and Reduced Kidney Function. J Am Soc Nephrol. 2019 Nov;30(11):2128-2139. doi: 10.1681/ASN.2018121250. Epub 2019 Aug 13. PMID: 31409727; PMCID: PMC6830793.
In vitro protocol:
1. Clerin V, Saito H, Filipski KJ, Nguyen AH, Garren J, Kisucka J, Reyes M, Jüppner H. Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion. J Clin Invest. 2020 Dec 1;130(12):6510-6522. doi: 10.1172/JCI135665. PMID: 32853180; PMCID: PMC7685737.
2. Thomas L, Xue J, Tomilin VN, Pochynyuk OM, Dominguez Rieg JA, Rieg T. PF-06869206 is a selective inhibitor of renal Pi transport: evidence from in vitro and in vivo studies. Am J Physiol Renal Physiol. 2020 Sep 1;319(3):F541-F551. doi: 10.1152/ajprenal.00146.2020. Epub 2020 Aug 3. PMID: 32744087; PMCID: PMC7509280.
In vivo protocol:
1. Clerin V, Saito H, Filipski KJ, Nguyen AH, Garren J, Kisucka J, Reyes M, Jüppner H. Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion. J Clin Invest. 2020 Dec 1;130(12):6510-6522. doi: 10.1172/JCI135665. PMID: 32853180; PMCID: PMC7685737.
2. Thomas L, Xue J, Murali SK, Fenton RA, Dominguez Rieg JA, Rieg T. Pharmacological Npt2a Inhibition Causes Phosphaturia and Reduces Plasma Phosphate in Mice with Normal and Reduced Kidney Function. J Am Soc Nephrol. 2019 Nov;30(11):2128-2139. doi: 10.1681/ASN.2018121250. Epub 2019 Aug 13. PMID: 31409727; PMCID: PMC6830793.
1: Shin S, Awuah Boadi E, Bandyopadhyay BC. Ablation of TRPC3 compromises bicarbonate and phosphate transporter activity in mice proximal tubular cells. Clin Exp Pharmacol Physiol. 2023 Mar;50(3):247-255. doi: 10.1111/1440-1681.13741. Epub 2022 Dec 18. PMID: 36433745; PMCID: PMC10258833.
2: Xue J, Thomas L, Dominguez Rieg JA, Rieg T. Sodium phosphate cotransporter 2a inhibitors: potential therapeutic uses. Curr Opin Nephrol Hypertens. 2022 Sep 1;31(5):486-492. doi: 10.1097/MNH.0000000000000828. Epub 2022 Jul 18. PMID: 35894284; PMCID: PMC9387751.
3: Thomas L, Dominguez Rieg JA, Rieg T. Npt2a as a target for treating hyperphosphatemia. Biochem Soc Trans. 2022 Feb 28;50(1):439-446. doi: 10.1042/BST20211005. PMID: 34994388; PMCID: PMC9022968.
4: Clerin V, Saito H, Filipski KJ, Nguyen AH, Garren J, Kisucka J, Reyes M, Jüppner H. Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion. J Clin Invest. 2020 Dec 1;130(12):6510-6522. doi: 10.1172/JCI135665. PMID: 32853180; PMCID: PMC7685737.
5: Thomas L, Xue J, Tomilin VN, Pochynyuk OM, Dominguez Rieg JA, Rieg T. PF-06869206 is a selective inhibitor of renal Pi transport: evidence from in vitro and in vivo studies. Am J Physiol Renal Physiol. 2020 Sep 1;319(3):F541-F551. doi: 10.1152/ajprenal.00146.2020. Epub 2020 Aug 3. PMID: 32744087; PMCID: PMC7509280.
6: Thomas L, Xue J, Murali SK, Fenton RA, Dominguez Rieg JA, Rieg T. Pharmacological Npt2a Inhibition Causes Phosphaturia and Reduces Plasma Phosphate in Mice with Normal and Reduced Kidney Function. J Am Soc Nephrol. 2019 Nov;30(11):2128-2139. doi: 10.1681/ASN.2018121250. Epub 2019 Aug 13. PMID: 31409727; PMCID: PMC6830793.
7: Filipski KJ, Sammons MF, Bhattacharya SK, Panteleev J, Brown JA, Loria PM, Boehm M, Smith AC, Shavnya A, Conn EL, Song K, Weng Y, Facemire C, Jüppner H, Clerin V. Discovery of Orally Bioavailable Selective Inhibitors of the Sodium- Phosphate Cotransporter NaPi2a (SLC34A1). ACS Med Chem Lett. 2018 Apr 12;9(5):440-445. doi: 10.1021/acsmedchemlett.8b00013. PMID: 29795756; PMCID: PMC5949730.
