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Publication Number
US-9980961-B2
Publication Date
2018-05-29
Expiration Date
Abstract
Described herein are methods for using compounds that activate pyruvate kinase.
Core Innovation
The invention describes formula (I) compounds and pharmaceutical compositions that activate wild-type and mutant pyruvate kinase R. The independent claim covers a method of activating a 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. Disclosed mutant pyruvate kinase R variants include those with impaired catalytic efficiency, FBP response, or thermostability.
The description documents structural variations, candidate compound structures, and analogs across formula (I) linkers, aryl and heteroaryl substituents, and structural parameters. Background problem, disease context, and therapeutic rationale are not explicitly described in patent. The disclosure identifies pyruvate kinase R deficiency, related anemias, sickle cell disease, blood-cell lifespan, and 2,3-DPG regulation as proposed areas of use.
Claims Coverage
The provided claims identify one independent claim directed to activating mutant pyruvate kinase R in a subject using a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising two inventive features.
Activation of mutant pyruvate kinase R
The method activates a mutant pyruvate kinase R in a subject in need thereof by administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof. Dependent claims identify specific mutant pyruvate kinase R variants, including G332S, G364D, T384M, R479H, R479K, R486W, R532W, R510Q, and R490W.
Compound of formula (I)
The administered agent is a compound of formula (I) or a pharmaceutically acceptable salt thereof, defined by specified alternatives for ring atoms, linkers L, substituents, and structural parameters, including optionally substituted aryl or heteroaryl for A.
The independent claim covers activating mutant pyruvate kinase R in a subject through administration of a therapeutically effective amount of a structurally defined formula (I) compound or its pharmaceutically acceptable salt, with dependent claims further defining compound substituents and specific mutant PKR variants.
Stated Advantages
Not explicitly described in patent.
Documented Applications
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, including identified mutant PKR variants.
Proposed use in pyruvate kinase R deficiency and related anemia, including hereditary non-spherocytic hemolytic anemia.
Proposed use in sickle cell disease, including sickle cell anemia.
Proposed use in regulating blood-cell lifespan and 2,3-DPG regulation.
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