| Autor: |
Henderson, Scott H., Sorrell, Fiona, Bennett, James, Fedorov, Oleg, Hanley, Marcus T., Godoi, Paulo H., Ruela de Sousa, Roberta, Robinson, Sean, Ashall-Kelly, Alexander, Hopkins Navratilova, Iva, Walter, Daryl S., Elkins, Jonathan M., Ward, Simon E. |
| Zdroj: |
Journal of Medicinal Chemistry; August 2021, Vol. 64 Issue: 15 p11709-11728, 20p |
| Abstrakt: |
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 11exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11in an in vivosetting. 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. |
| Databáze: |
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