Mitapivat

Mitapivat is a first-in-class pyruvate kinase activator and certified reference standard developed for the treatment of pyruvate kinase deficiency in adults. As the active pharmaceutical ingredient marketed as Pyrukynd®, Mitapivat received FDA approval in 2022 for this indication, representing a major advance in the management of this rare disease. In pharmaceutical quality control contexts, Mitapivat serves as the primary reference standard for impurity profiling, analytical method development, and regulatory submissions. Mitapivat is recognized through multiple regulatory designations including INN and USAN, making it indispensable for ANDA filings and quality control testing. The drug substance Mitapivat exhibits excellent stability when stored under recommended conditions. Furthermore, Mitapivat functions as an allosteric activator of pyruvate kinase, demonstrating the therapeutic potential of this well-characterized molecular scaffold in rare disease treatment.

Product Parameters

Application

Mitapivat (brand name: Pyrukynd) is a first-in-class novel drug developed by Agios Pharmaceuticals, Inc., which acts as an oral pyruvate kinase activator. Mitapivat has been approved in both the European Union and the United States for the treatment of hemolytic anemia and pyruvate kinase deficiency (PKD)—a rare genetic disorder associated with chronic hemolytic anemia. Prior to the availability of mitapivat, the clinical management of PKD was limited to supportive care, including therapies such as red blood cell transfusions and splenectomy, which carry both short-term and long-term risks.

Synthetic Route

The synthesis of mitapivat involves two steps for the preparation of sulfonamide 9.7: first, sulfonyl chloride 9.4 reacts with aniline 9.5 to yield ester 9.6 at a 99% yield (Figure 2.4.2); next, ester 9.6 is hydrolyzed under basic conditions to obtain carboxylic acid 9.7, with a ChemicalBook reported yield of 91%. The carboxylic acid 9.7 is then activated via CDI treatment, followed by the addition of piperazine 9.3, resulting in an efficient coupling reaction at the kilogram scale. Finally, water is added to the reaction mixture to induce crystallization of the product, yielding mitapivat at a 90% isolated yield.

Bioactivity

Mitapivat (AG-348) is an activator of pyruvate kinase PKM2, which participates in glycolysis.