Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

Scott H. Henderson (Lead / Corresponding author), Fiona Sorrell, James Bennett, Oleg Fedorov, Marcus T. Hanley, Paulo H. Godoi, Roberta Ruela de Sousa, Sean Robinson, Alexander Ashall-Kelly, Iva Hopkins Navratilova, Daryl S. Walter, Jonathan M. Elkins (Lead / Corresponding author), Simon E. Ward (Lead / Corresponding author)

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    Abstract

    Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

    Original languageEnglish
    Pages (from-to)11709-11728
    Number of pages20
    JournalJournal of Medicinal Chemistry
    Volume64
    Issue number15
    Early online date3 Aug 2021
    DOIs
    Publication statusPublished - 12 Aug 2021

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