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Publication Number
US-11793806-B2
Publication Date
2023-10-24
Expiration Date
Abstract
Described herein are methods for using compounds that activate pyruvate kinase.
Core Innovation
The invention relates to pyruvate kinase (PKR) activator compounds for treating red blood cell (RBC) disorders associated with pyruvate kinase deficiency (PKD). The disclosed rationale describes PKD pathophysiology including ATP depletion and altered 2,3-diphosphoglycerate (2,3-DPG), leading to hemolytic anemia with reduced RBC lifetime. The disclosure proposes that activating pyruvate kinase increases RBC lifetime and modulates 2,3-DPG.
The disclosure further links PKR activation to an antisickling rationale by shifting the oxygenhemoglobin equilibrium to reduce sickling, supported by the described relationship between oxygenhemoglobin dissociation and 2,3-DPG. In this context, PKR activation is positioned as a therapeutic approach for hemolytic anemia conditions beyond PKD, including sickle cell anemia and hereditary non-spherocytic hemolytic anemia (HNSHA).
Therapeutic methods are described as administering compounds that are described by a structural formula (Formula (I) with defined substituent and linkage variables) or pharmaceutically acceptable salts. The disclosure also specifies representative PKR mutants and notes activation of mutant and wild-type PKR in connection with restoring catalytic efficiency, thermostability, or FBP responsiveness, together with brief assay references.
The described chemical matter includes variable structural features W, X, Y, and Z; aryl or heteroaryl group A; linkage L; substituent R1; and substituents R3, Ra, Rb, Rc, and Rd with defined index ranges n, m, h, and g. The document includes representative chemical structures and defines pharmaceutically acceptable salts, as well as formulation and salt/isomer definitions within the disclosed scope.
Claims Coverage
The document provides two independent claims covering methods for increasing the lifetime of red blood cells (RBCs) in subjects, with distinct scope defined by (i) a broad Formula I structural class and (ii) a specific named compound, each limited to pyruvate kinase deficiency (PKD).
Increasing RBC lifetime in PKD using Formula I compounds
A method for increasing the lifetime of red blood cells (RBCs) in a subject having pyruvate kinase deficiency (PKD) by administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, where the compound is defined by the specific structural variable constraints including W, X, Y, Z, D and D1, A, L, R1, R3, Ra, Rb, Rc, Rd, and indices n, m, h, and g.
Increasing RBC lifetime in PKD using a specific N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide compound
A method for increasing the lifetime of red blood cells (RBCs) in a subject having pyruvate kinase deficiency (PKD) by administering an effective amount of the specific compound N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage centers on increasing RBC lifetime in subjects with pyruvate kinase deficiency (PKD) using either a defined Formula I compound class with extensive structural-variable constraints or a specifically named N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide compound (or pharmaceutically acceptable salt).
Stated Advantages
Increases the lifetime of red blood cells (RBCs).
Modulates 2,3-diphosphoglycerate (2,3-DPG).
Shifts the oxygenhemoglobin equilibrium to reduce sickling.
Documented Applications
Treating red blood cell (RBC) disorders associated with pyruvate kinase deficiency (PKD), including methods for increasing RBC lifetime in subjects with PKD.
Sickle cell anemia is discussed in connection with an antisickling rationale based on shifting the oxygenhemoglobin equilibrium.
Hereditary non-spherocytic hemolytic anemia (HNSHA) is discussed as a condition beyond PKD for which PKR activation is positioned as therapeutically relevant.
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