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Publication Number
US-10632114-B2
Publication Date
2020-04-28
Expiration Date
Abstract
Described herein are methods for using compounds that activate pyruvate kinase.
Core Innovation
The disclosure describes formula (I) compounds and pharmaceutically acceptable salts functioning as pyruvate kinase R (PKR) activators. These compounds activate wild-type PKR and reduced-activity PKR mutants, restoring catalytic efficiency, FBP responsiveness, or thermostability, with representative compounds showing AC50 values below 500 nM. Small-molecule structures comprise recurring aryl and heteroaryl amide groups and sulfonamide motifs formulated alone or in pharmaceutically acceptable compositions with a carrier.
Methods concern treating sickle cell anemia, thalassemia, and specified hemolytic anemias, including congenital anemia and hereditary spherocytosis. The methods further encompass increasing red blood cell lifetime and regulating 2,3-diphosphoglycerate levels in blood by contacting blood in a subject or extracorporeally. The supplied claim text omits the specific chemical identity of the compound, and the technical problem is not explicitly described in the provided text.
Claims Coverage
The supplied claims contain five independent claims: claims 1, 2, 4, 7, and 10, covering five inventive features directed to treating specified anemias, increasing red blood cell survival, and modifying blood metabolite levels.
Treating sickle cell anemia
Claim 1 covers treating sickle cell anemia in a subject by administering a therapeutically effective amount of a compound, its pharmaceutically acceptable salt, or a pharmaceutically acceptable composition comprising the compound or salt and a pharmaceutically acceptable carrier, wherein the supplied claim text ends before identifying the compound.
Treating thalassemia
Claim 2 covers treating thalassemia in a subject by administering a therapeutically effective amount of a compound, its pharmaceutically acceptable salt, or a pharmaceutically acceptable composition comprising the compound or salt and a pharmaceutically acceptable carrier, with dependent claims specifying beta-thalassemia.
Increasing red blood cell lifetime
Claim 4 covers increasing the lifetime of red blood cells by contacting blood with a therapeutically effective amount of a compound, its pharmaceutically acceptable salt, or a pharmaceutically acceptable composition comprising the compound or salt and a carrier, including administration to a subject or extracorporeal addition to whole blood or packed red blood cells.
Regulating 2,3-diphosphoglycerate levels in blood
Claim 7 covers regulating 2,3-diphosphoglycerate levels in blood by contacting blood with an effective amount of a compound, its pharmaceutically acceptable salt, or a pharmaceutically acceptable composition comprising the compound or salt and a carrier, including administration to a subject or extracorporeal addition to whole blood or packed red blood cells.
Treating specified hemolytic anemia
Claim 10 covers treating hemolytic anemia in a subject by administering a therapeutically effective amount of a compound, its pharmaceutically acceptable salt, or a pharmaceutically acceptable composition comprising the compound or salt and a carrier, wherein the hemolytic anemia is selected from congenital anemia and hereditary spherocytosis.
The five independent claims cover methods for treating sickle cell anemia, thalassemia, and specified hemolytic anemias, as well as methods for increasing red blood cell lifetime and regulating 2,3-diphosphoglycerate levels in blood, with dependent claims adding specific administration routes and disease subtypes.
Stated Advantages
PKR activation is linked to regulating 2,3-DPG levels in blood.
PKR activation is linked to increasing red-blood-cell lifetime.
Documented Applications
Treatment of sickle cell anemia in a subject.
Treatment of thalassemia, including beta-thalassemia, in a subject.
Treatment of hemolytic anemia, specifically congenital anemia or hereditary spherocytosis, in a subject.
Increasing the lifetime of red blood cells, including through administration to a subject or direct extracorporeal addition to whole blood or packed red blood cells.
Regulating 2,3-diphosphoglycerate (2,3-DPG) levels in blood, including through administration to a subject or direct extracorporeal addition to whole blood or packed red blood cells.
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