TY - JOUR
T1 - Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors
AU - Henderson, Scott H.
AU - Sorrell, Fiona
AU - Bennett, James
AU - Fedorov, Oleg
AU - Hanley, Marcus T.
AU - Godoi, Paulo H.
AU - Ruela de Sousa, Roberta
AU - Robinson, Sean
AU - Ashall-Kelly, Alexander
AU - Hopkins Navratilova, Iva
AU - Walter, Daryl S.
AU - Elkins, Jonathan M.
AU - Ward, Simon E.
N1 - Funding - S.H.H. is funded by the BBSRC (BB/L017105/1). S.E.W. is funded by the Wellcome Trust, MRC, BBSRC and the European Structural Funding via Ser Cymru scheme. R.R.d.S. ̂ is funded by Sao Paulo Research Foundation-FAPESP 2016/ ̃17469-0 and 13/50724-5. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-FAPESP, Takeda, and Wellcome [106169/ZZ14/Z].
PY - 2021/8/12
Y1 - 2021/8/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85113707719&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c01115
DO - 10.1021/acs.jmedchem.1c01115
M3 - Article
C2 - 34342227
SN - 0022-2623
VL - 64
SP - 11709
EP - 11728
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 15
ER -
