acs.jmedchem.1c01115.pdf (3.66 MB)
Discovery and characterization of selective and ligand-efficient DYRK inhibitors
journal contribution
posted on 2023-06-10, 03:36 authored by Scott H Henderson, 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, Simon E WardDual-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.
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Publication status
- Published
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- Published version
Journal
Journal of Medicinal ChemistryISSN
0022-2623Publisher
American Chemical Society (ACS)External DOI
Issue
15Volume
64Page range
11709-11728Event location
United StatesDepartment affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-05-19First Open Access (FOA) Date
2022-05-19First Compliant Deposit (FCD) Date
2022-05-19Usage metrics
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