2227425-05-8 Usage
Description
(R)-3-chloro-7-(2-(hydroxymethyl)morpholino)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile, also known as PF-06869206, is an orally bioavailable inhibitor of sodium-phosphate cotransporter 2a (NaPi2a) with high selectivity. It exhibits potent inhibition of NaPi2a with an IC50 value of 380 nM, while showing minimal inhibition against other related transporters such as NaPi2b, NaPi2c, PiT-1, and PiT-2 (IC50s > 25 μM). (R)-3-chloro-7-(2-(hydroxymethyl)morpholino)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile is characterized by its unique molecular structure, which includes a chloro, hydroxymethylmorpholino, and trifluoromethyl group, contributing to its selective binding and inhibitory properties.
Uses
Used in Pharmaceutical Industry:
PF-06869206 is used as a therapeutic agent for the treatment of conditions related to phosphate regulation. Its high selectivity for NaPi2a makes it a promising candidate for the development of targeted therapies that can modulate phosphate levels in the body, potentially benefiting patients with disorders characterized by abnormal phosphate metabolism.
Used in Research Applications:
In the field of biomedical research, PF-06869206 serves as a valuable tool for studying the role of NaPi2a in various physiological and pathological processes. By selectively inhibiting this transporter, researchers can gain insights into the underlying mechanisms of phosphate homeostasis and its impact on health and disease.
Used in Drug Development:
PF-06869206 is utilized in the development of novel pharmaceuticals targeting sodium-phosphate cotransporters. Its high selectivity and potency make it an attractive starting point for designing new drugs that can effectively regulate phosphate levels, which may be beneficial in treating a range of conditions, from kidney diseases to certain types of cancer.
In Vivo
PF-06869206 is evaluated in rodent PK studies to determine suitability for in vivo pharmacology exploration. Results show moderate clearance in both rat and mouse. Oral bioavailability at 5 mg/kg is good in rat and moderate in mouse. At higher oral doses of 50 mg/kg, supraproportional increases in exposure are observed in both species, suggestive of saturation of clearance. PF-06869206 has moderate terminal elimination half-life (t1/2=1.35 h, and 0.75 h for Wistar-Han rats (10 mg/kg, iv), and C57BL6 mice (1 mg/kg, iv)). Furthermore, permeability is good (14×10-6?cm/s), and rat liver microsome (RLM) clearance is low (<14 μL/min/mg; HLM=39 μL/min/mg).
Biological Activity
PF-06869206 (PF06869206) is a potent, selective, orally bioavailable inhibitor of sodium-phosphate cotransporter 2a (NaPi2a/SLC34A1) with IC50 of 380 nM, no inhibition against NaPi2b (SLC34A2) and NaPi2c (SLC34A3).PF-06869206 displays excellent subtype selectivity against other sodium-phosphate cotransporters: NaPi2b, NaPi2c, PiT-1, and PiT-2 (SLC20A2).PF-06869206 showed comparable submicromolar activity for the human, rat, and mouse NaPi2a isoforms (IC50=0.4-0.54 uM) and was selective over rodent NaPi2c, inhibited phosphate uptake in human proximal tubule cells.PF-06869206 was well tolerated and elicited a dose-dependent increase in fractional phosphate excretion, lowered plasma phosphate levels in WT mice and in rats with chronic kidney disease (CKD), induced an unabated acute phosphaturic and hypophosphatemic effect in CKD rats.
in vitro
PF-06869206 shows a balance of attributes with 380 nM NaPi2a inhibition potency, excellent subtype selectivity, and acceptable aqueous solubility (46 μM). PF-06869206 is profiled for potency in the rodent NaPi2a and NaPi2c cell lines. PF-06869206 shows comparable submicromolar activity for the human, rat, and mouse NaPi2a isoforms with IC50s of 0.4±0.047 μM and 0.54±0.099 μM for rat NaPi2a and mouse NaPi2a, respectively.
Check Digit Verification of cas no
The CAS Registry Mumber 2227425-05-8 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 2,2,2,7,4,2 and 5 respectively; the second part has 2 digits, 0 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 2227425-05:
(9*2)+(8*2)+(7*2)+(6*7)+(5*4)+(4*2)+(3*5)+(2*0)+(1*5)=138
138 % 10 = 8
So 2227425-05-8 is a valid CAS Registry Number.
2227425-05-8Relevant articles and documents
Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1)
Filipski, Kevin J.,Sammons, Matthew F.,Bhattacharya, Samit K.,Panteleev, Jane,Brown, Janice A.,Loria, Paula M.,Boehm, Markus,Smith, Aaron C.,Shavnya, Andre,Conn, Edward L.,Song, Kun,Weng, Yan,Facemire, Carie,Jüppner, Harald,Clerin, Valerie
supporting information, p. 440 - 445 (2018/05/23)
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. Herein, we detail the discovery of the first series of selective NaPi2a inhibitors, resulting from optimization of a high-throughput screening hit. The oral PK profile of inhibitor PF-06869206 (6f) in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.
