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Discovery and characterization of selective and ligand-efficient DYRK inhibitors

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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 Ward
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Medicinal Chemistry

ISSN

0022-2623

Publisher

American Chemical Society (ACS)

Issue

15

Volume

64

Page range

11709-11728

Event location

United States

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2022-05-19

First Open Access (FOA) Date

2022-05-19

First Compliant Deposit (FCD) Date

2022-05-19

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