Activators of human pyruvate kinase
Inventors
Thomas, Craig J. • Auld, Douglas S. • Inglese, James • Skoumbourdis, Amanda P. • Jiang, Jian-Kang • Boxer, Matthew B.
Assignees
US Department of Health and Human Services
Publication Number
US-8937067-B2
Publication Date
2015-01-20
Expiration Date
2029-10-09
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed are pyruvate kinase M2 activators, which are, bis sulfonamide piperazinyl compounds of Formula (I) and 2,4-disubstituted 4H-thieno[3,2-b]pyrrole-2-(substituted benzyl)pyridazin-3(2H)ones of Formula (II), wherein L and R1 to R16 are as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer and anemia,
Core Innovation
The invention provides activators of the M2 isoform of human pyruvate kinase (PKM2), specifically bis sulfonamide piperazinyl compounds of Formula (I) and 2,4-disubstituted 4H-thieno[3,2-b]pyrrole-2-(substituted benzyl)pyridazin-3(2H)ones of Formula (II). These compounds are useful in treating diseases that respond to activation of PKM2, such as cancer and anemia. The invention also includes pharmaceutical compositions comprising these compounds and methods of using the compounds as therapeutic agents.
The problem being addressed is that PKM2 is expressed and re-expressed in tumors and plays a crucial role in the metabolic transformation of tumor cells required for rapid cell growth and proliferation. PKM2 activity is downregulated in cancer cells, leading to a build-up of glycolytic intermediates that can be diverted towards biosynthesis necessary for cell growth. Additionally, PK deficiency causes hemolytic anemia due to metabolic blocks in red blood cells, and modulation of PKM2 could offer therapeutic benefit. Therefore, there is a desire for new activators of PKM2 to treat such diseases.
Claims Coverage
The patent discloses one independent claim directed to compounds of Formula II and their pharmaceutically acceptable salts, including pharmaceutical compositions containing such compounds. There are multiple dependent claims specifying substituents and preferred embodiments related to Formula II compounds.
Compounds of Formula II with defined substituents
The claim covers compounds of Formula II with R11 selected from hydrogen, C1-C10 alkyl, various substituted groups including OR17, SR17, SOR17, SO2R17, NR17R18, NCOR17, SCOR17, COR17, OCOR17, B(OH)2, NO2, NHCOR17, CN, CHO, hydroxy C1-C10 alkyl, and halogen. R12 is selected from hydrogen, C1-C2 alkyl, C3-C10 cycloalkyl, NCOR14, and SO2R14. R13 to R16 include H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and various other substituents. R17 and R18 are independently selected from hydrogen and C1-C10 alkyl.
Pharmaceutical compositions containing compounds of Formula II
Claims include pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound or salt of Formula II with the substituents defined in claim 1.
Specific preferred substituents for enhanced properties
Certain claims specify preferred substituents such as R11 and R12 being methyl, R13 being 2-fluoro, chloro, or other halogen substituted phenyl groups, and other preferred patterns of substitution yielding compounds with improved potency or selectivity.
The claims primarily cover compounds of Formula II featuring specific substituents that activate human PKM2, their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and preferred structural variants to optimize therapeutic properties.
Stated Advantages
The compounds activate PKM2 by increasing the enzyme's affinity for phosphoenolpyruvate (PEP) without significantly affecting ADP kinetics.
They show high selectivity for PKM2 over other pyruvate kinase isoforms such as PKM1, PKL, and PKR.
Lead compounds demonstrate good potency and efficacy in biochemical assays.
Documented Applications
Treatment or prevention of cancer, including renal cancer, ovarian cancer, breast cancer, CNS cancer, leukemia, prostate cancer, non-small cell lung cancer, colon cancer, and melanoma.
Treatment of certain forms of anemia associated with downregulation of the R form of pyruvate kinase, such as human erythrocyte R-type pyruvate kinase deficiency.
Interested in licensing this patent?