ChemicalBook CAS DataBase List 1260075-17-9

1260075-17-9

Name	PKR-IN-1
CAS	1260075-17-9
EINECS(EC#)	604-604-1
Molecular Formula	C24H26N4O3S
MDL Number	MFCD26936342
Molecular Weight	450.55
MOL File	1260075-17-9.mol

Chemical Properties

Boiling point	667.3±65.0 °C(Predicted)
density	1.369±0.06 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	DMSO : 50 mg/mL (110.98 mM)
form	Solid
pka	6.69±0.50(Predicted)
color	White to off-white

Safety Data

Symbol(GHS)	GHS07
Signal word	Warning
Hazard statements	H302-H315-H319-H335
Precautionary statements	P261-P305+P351+P338

Hazard Information

Description

Mitapivat (trade name Pyrukynd) is a first-in-class drug developed by Agios Pharmaceuticals, Inc. It is an oral activator of red blood cell pyruvate kinase. Mitapivat is approved in the European Union and the United States for the treatment of hemolytic anemia and pyruvate kinase deficiency (PKD), a rare genetic disease associated with chronic hemolytic anemia. Clinical management of PKD was previously limited to supportive care, including red blood cell transfusions and splenectomy, which have short-term and long-term risks.

Uses

Mitapivat (AG-348) is an orally active pyruvate kinase allosteric activator. Mitapivat increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes, shows the potential to restore the activity of PK (pyruvate kinase)-deficient glycolytic pathways. Mitapivat can be used in study of PK deficiency[1][2][3].

Synthesis

The second building block of Mitapivat, sulfonamide 9.7, was prepared in two steps. First, sulfonyl chloride 9.4 was reacted with aniline 9.5 to give ester 9.6 in 99% yield (Figure 2.4.2). Ester 9.6 was hydrolyzed under alkaline conditions to give carboxylic acid 9.7 in 91% yield. Efficient coupling on a kilogram scale was achieved by activation of carboxylic acid 9.7 using CDI followed by addition of piperazine 9.3. Finally, water was added to the reaction mixture to induce crystallization of the product, giving mitapitant in 90% isolated yield.
Mitapivat

in vivo

Mitapivat (50 mg/kg; p.o.; twice daily for 21 days) improves anemia in a mouse model for β-thalassemia^[2].

Animal Model:	WT C57B6 and Hbb^th3/+ mice (both are 2-month-old female mice; β-thalassemia model)^[2].
Dosage:	50 mg/kg
Administration:	In animal feedings; single daily for 3 weeks.
Result:	Increased the expression of pyruvate kinase isoforms in both red cells and erythroid precursors from Hbbth^3/+ mice. Elevated pyruvate kinase activity in cells from Hbbth^3/+ mice, and markedly increased ROS level in erythrocytes. Increased the expression of PKM2 in polychromatic and orthochromatic erythroblasts of Hbbth^3/+ mice.

Animal Model:	WT C57B6 and Hbb^th3/+ mice (both are 2-month-old female mice; β-thalassemia model)^[2].
Dosage:	50 mg/kg
Administration:	Oral gavage, twice daily for 21 days.
Result:	Ameliorated ineffective erythropoiesis and anemia in Hbb^th3/+ mice and increased ATP, reduced ROS production, as well as reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance.

References

[1] Kung C, et al. AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency. Blood. 2017 Sep 14;130(11):1347-1356. DOI:10.1182/blood-2016-11-753525
[2] Matte A, et al. The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model. J Clin Invest. 2021 May 17;131(10):e144206. DOI:10.1172/JCI144206
[3] Rab MAE, et al. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. DOI:10.3324/haematol.2019.238865

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