| Identification | Back Directory | [Name]
PKR-IN-1 | [CAS]
1260075-17-9 | [Synonyms]
ag348
AG-348
CS-2722
PKR-IN-1
Mitapivat
PKM2 activator
cas 1260075-17-9
AG348;AG348;AG-348
PKM2 activator 1020
MITAPIVAT;PKM2 ACTIVATOR;CAS 1260075-17-9
N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
N-(4-{[4-(Cyclopropylmethyl)-1-piperazinyl]carbonyl}phenyl)-8-quinolinesulfonamide
8-Quinolinesulfonamide, N-[4-[[4-(cyclopropylmethyl)-1-piperazinyl]carbonyl]phenyl]- | [EINECS(EC#)]
604-604-1 | [Molecular Formula]
C24H26N4O3S | [MDL Number]
MFCD26936342 | [MOL File]
1260075-17-9.mol | [Molecular Weight]
450.55 |
| Chemical Properties | Back Directory | [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 |
| Hazard Information | Back Directory | [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]
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 Hbbth3/+ 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 Hbbth3/+ mice.
Elevated pyruvate kinase activity in cells from Hbbth3/+ mice, and markedly increased ROS level in erythrocytes.
Increased the expression of PKM2 in polychromatic and orthochromatic erythroblasts of Hbbth3/+ mice.
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| Animal Model: | WT C57B6 and Hbbth3/+ 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 Hbbth3/+ 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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