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Publication Number
US-12377093-B2
Publication Date
2025-08-05
Expiration Date
Abstract
Described herein are methods for using compounds that activate pyruvate kinase.
Core Innovation
The innovation provides methods of activating pyruvate kinase R or mutant pyruvate kinase R in a subject in need thereof. Each method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds address reduced pyruvate kinase R activity, including impaired catalytic efficiency, responsiveness to FBP, or thermostability in mutants. The claimed formula defines alternatives for ring atoms, linkages, aryl or heteroaryl groups, linkers, substituents, and structural variables.
The compounds activate wild-type pyruvate kinase R as well as reduced-activity mutants, including R532W, R479H, and G332S. Documented uses include administering these agents to treat hereditary and other hemolytic anemias, sickle cell disease, and thalassemia. The methods further encompass extending red-cell lifetime and regulating blood 2,3-DPG levels in a subject.
Claims Coverage
The independent claims set forth two inventive features directed to methods of activating pyruvate kinase R and mutant pyruvate kinase R using a formula (I) compound or pharmaceutically acceptable salt thereof.
Activation of pyruvate kinase R
A method of activating pyruvate kinase R in a subject in need thereof by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, defined through alternatives for ring atoms, linkages, aryl or heteroaryl groups, linkers, substituents, and subscript values.
Activation of mutant pyruvate kinase R
A method of activating mutant pyruvate kinase R in a subject in need thereof by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, defined through alternatives for ring atoms, linkages, aryl or heteroaryl groups, linkers, substituents, and subscript values.
The independent claims cover the activation of pyruvate kinase R and mutant pyruvate kinase R in a subject in need thereof using structurally defined formula (I) compounds or their pharmaceutically acceptable salts.
Stated Advantages
The compounds activate wild-type PKR and reduced-activity PKR mutants, addressing impaired catalytic efficiency, FBP responsiveness, or thermostability.
Documented Applications
Activating pyruvate kinase R, including mutant pyruvate kinase R, in a subject in need thereof.
Treatment of hereditary and other hemolytic anemias, sickle cell disease, and thalassemia.
Extending red-cell lifetime.
Regulating blood 2,3-DPG levels in a subject.
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