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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 publication

DOI

10.1021/acs.jmedchem.1c01115

Type

Journal article

Journal

J Med Chem

Publication Date

12/08/2021

Volume

64

Pages

11709 - 11728

Keywords

Dose-Response Relationship, Drug, Drug Discovery, HEK293 Cells, Humans, Ligands, Molecular Structure, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Solubility, Structure-Activity Relationship, Dyrk Kinases