| Full text | |
| Author(s): Show less - |
Henderson, Scott H.
[1, 2]
;
Sorrell, Fiona
[3]
;
Bennett, James
[4]
;
Fedorov, Oleg
[4]
;
Hanley, Marcus T.
[5]
;
Godoi, Paulo H.
[6]
;
de Sousa, Roberta Ruela
[6]
;
Robinson, Sean
[7]
;
Ashall-Kelly, Alexander
[5]
;
Navratilova, Iva Hopkins
[7, 8]
;
Walter, Daryl S.
[9]
;
Elkins, Jonathan M.
[3, 6]
;
Ward, Simon E.
[5]
Total Authors: 13
|
| Affiliation: | [1] Univ Sussex, Sussex Drug Discovery Ctr, Brighton BN1 9RH, E Sussex - England
[2] BenevolentAI, Minerva Bldg, Babraham Hall, Cambridge CB22 3AT - England
[3] Univ Oxford, Struct Genom Consortium, Oxford OX3 7DQ - England
[4] Univ Oxford, Target Discovery Inst, Oxford OX3 7FZ - England
[5] Cardiff Univ, Med Discovery Inst, Cardiff CF10 3AT - Wales
[6] Univ Estadual Campinas, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil
[7] Exscientia, Oxford OX4 4GE - England
[8] Univ Dundee, Dundee DD1 5EH - Scotland
[9] Evotec UK Ltd, Abingdon OX14 4RZ, Oxon - England
Total Affiliations: 9
|
| Document type: | Journal article |
| Source: | Journal of Medicinal Chemistry; v. 64, n. 15, p. 11709-11728, AUG 12 2021. |
| Web of Science Citations: | 0 |
| 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. (AU) | |
| FAPESP's process: | 16/17469-0 - Development of celular assays to measure and to discover the phenotypic consequences of chemical inhibition of Vaccinia-Related Kinase 1 (VRK1) |
| Grantee: | Roberta Regina Ruela de Sousa |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research |
| Grantee: | Paulo Arruda |
| Support Opportunities: | Research Grants - Research Partnership for Technological Innovation - PITE |