Discovery and characterization of selective and ligand-efficient DYRK inhibitors

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. and Ward, Simon E. ORCID: https://orcid.org/0000-0002-8745-8377 2021. Discovery and characterization of selective and ligand-efficient DYRK inhibitors. Journal of Medicinal Chemistry 64 (15) , 11709–11728. 10.1021/acs.jmedchem.1c01115

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	17 February 2022
Date of Acceptance:	21 June 2021
Last Modified:	08 May 2023 00:26
URI:	https://orca.cardiff.ac.uk/id/eprint/147588

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