Mitapivat 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)

pka

6.69±0.50(Predicted)

form 

Solid

color 

White to off-white

InChI

InChI=1S/C24H26N4O3S/c29-24(28-15-13-27(14-16-28)17-18-6-7-18)20-8-10-21(11-9-20)26-32(30,31)22-5-1-3-19-4-2-12-25-23(19)22/h1-5,8-12,18,26H,6-7,13-17H2

InChIKey

XAYGBKHKBBXDAK-UHFFFAOYSA-N

SMILES

N1C2C(=CC=CC=2S(NC2=CC=C(C(N3CCN(CC4CC4)CC3)=O)C=C2)(=O)=O)C=CC=1

Mitapivat Usage And Synthesis

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.

in vivo

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