Pyruvate kinase activators for use in treating blood disorders
Inventors
Cianchetta, Giovanni • Liu, Tao • Padyana, Anil Kumar • Sui, Zhihua • Cai, Zhenwei • Cui, DaWei • Ji, Jingjing
Assignees
PHARMARESOURCES (SHANGHAI) CO Ltd • Agios Pharmaceuticals Inc
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Publication Number
US-11040036-B2
Publication Date
2021-06-22
Expiration Date
Abstract
Described herein are compounds that activate pyruvate kinase, pharmaceutical compositions and methods of use thereof. These compounds are represented by Formula (I) wherein R1, R2, Ra, Rb, Rj, Rk, and Q are as defined herein.
Core Innovation
The disclosed subject matter encompasses a structurally defined genus of thiazolo[5′,4′:4,5]pyrrolo[2,3-d]pyridazin-5-one compounds, or pharmaceutically acceptable salts thereof. The structural formula defines substituent Q as an optionally substituted six-membered monocyclic heteroaryl group alongside defined alternatives for substituents R1, Ra, Rb, Rj, Rk, Rp, Rn6, and q. These substituent definitions encompass alkyl, aryl, heterocyclyl, heteroaryl, oxygen-containing, and sulfur-containing moieties, with options to form specified rings or carbonyl groups.
The disclosed compounds operate as activators of wild-type and mutant pyruvate kinase R, including the K410E and R510Q mutant variants. Disclosed examples demonstrate substituted analogs characterized by LCMS and 1H NMR, alongside assay formats including red blood cell-based ATP measurements. The text lacks explicit background problem statements and quantitative efficacy outcomes.
Claims Coverage
The provided claims identify one independent claim directed to a structurally defined compound genus or a pharmaceutically acceptable salt thereof, comprising one inventive feature.
Structurally defined compound genus and pharmaceutically acceptable salt
Claim 1 recites a compound represented by the structural formula, or a pharmaceutically acceptable salt thereof, comprising an optionally substituted 6-membered monocyclic heteroaryl Q, designated alternatives for substituents R1, Ra, Rb, Rj, Rk, Rp, and Rn6, and q values of 0, 1, 2, or 3, including options for substituents to form specified rings or a carbonyl group.
The independent claim covers the structurally defined compound genus and pharmaceutically acceptable salts thereof, with scope defined by all elements of the claim.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Activation of wild-type and mutant pyruvate kinase R (PKR), including variants K410E and R510Q, for regulating red-cell lifespan and 2,3-diphosphoglycerate levels.
Pharmaceutical compositions for the treatment of pyruvate kinase deficiency, sickle cell disease, anemia, hemolytic anemia, and thalassemia.
PKR wild-type and mutant activation assay formats and red blood cell-based ATP assays.
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