Developing novel classes of protein kinase CK1δ inhibitors by fusing [1,2,4]triazole with different bicyclic heteroaromatic systems.

Abstract

Protein kinase CK1δ expression and activity is involved in different pathological situations that include neuroinflammatory and neurodegenerative diseases. For this reason, protein kinase CK1δ has become a possible therapeutic target for these conditions. 5,6-fused bicyclic heteroaromatic systems that resemble adenine of ATP represent optimal scaffolds for the development of a new class of ATP competitive CK1δ inhibitors. In particular, a new series of [1,2,4]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-a][1,3,5]triazines was developed. Some crucial interactors have been identified, such as the presence of a free amino group able to interact with the residues of the hinge region at the 5- and 7- positions of the [1,2,4]triazolo[1,5-c]pyrimidine and [1,2,4]triazolo[1,5-a][1,3,5]triazine scaffolds, respectively; or the presence of a 3-hydroxyphenyl or 3,5-dihydroxyphenyl moiety at the 2- position of both nuclei. Molecular modeling studies identified the key interactions involved in the inhibitor-protein recognition process that appropriately fit with the outlined structure-activity relationship. Considering the fact that the CK1 protein kinase is involved in various pathologies in particular of the central nervous system, the interest in the development of new inhibitors permeable to the blood-brain barrier represents today an important goal in the pharmaceutical field. The best potent compound of the series is the 5-(7-amino-5-(benzylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)benzen-1,3-diol (compound 51, IC50 = 0.18 μM) that was predicted to have an intermediate ability to cross the membrane in our in vitro assay and represents an optimal starting point to both studies the therapeutic value of protein kinase CK1δ inhibition and to develop new more potent derivatives.

• Authors: Ilenia Grieco, Maicol Bissaro, Davide Benedetto Tiz, Daniel I Perez, Conception Perez, Ana Martinez, Sara Redenti, Elena Mariotto, Roberta Bortolozzi, Giampietro Viola, Giorgio Cozza, Giampiero Spalluto, Stefano Moro, Stephanie Federico
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 216 Pg. 113331 (Apr 15 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33721670 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Pyrimidines
• Triazines
• Triazoles
• Casein Kinase Idelta
• pyrimidine

Topics

• Binding Sites
• Blood-Brain Barrier (drug effects, metabolism)
• Casein Kinase Idelta (antagonists & inhibitors, metabolism)
• Cell Line
• Cell Survival (drug effects)
• Drug Design
• Humans
• Kinetics
• Molecular Docking Simulation
• Protein Kinase Inhibitors (chemistry, metabolism, pharmacology)
• Pyrimidines (chemistry)
• Static Electricity
• Structure-Activity Relationship
• Thermodynamics
• Triazines (chemistry)
• Triazoles (chemistry, metabolism, pharmacology)