1,4,6-Trisubstituted imidazo[4,5-c]pyridines as inhibitors of Bruton's tyrosine kinase

0545764 - ÚEB 2022 RIV FR eng J - Journal Article
Krajčovičová, S. - Jorda, Radek - Vanda, D. - Soural, M. - Kryštof, Vladimír
1,4,6-Trisubstituted imidazo[4,5-c]pyridines as inhibitors of Bruton's tyrosine kinase.
European Journal of Medicinal Chemistry. Roč. 211, FEB 5 (2021), č. článku 113094. ISSN 0223-5234. E-ISSN 1768-3254
Institutional support: RVO:61389030
Keywords : Bruton's tyrosine kinase * imidazo[4,5-c]pyridine * Inhibitor * Protein kinase
OECD category: Technologies involving identifying the functioning of DNA, proteins and enzymes and how they influence the onset of disease and maintenance of well-being (gene-based diagnostics and therapeutic interventions (pharmacogenomics, gene-based therapeutics)
Impact factor: 7.088, year: 2021
Method of publishing: Open access
http://doi.org/10.1016/j.ejmech.2020.113094

Herein, we report an efficient synthetic approach towards trisubstituted imidazo [4,5-c]pyridines designed as inhibitors of Bruton's tyrosine kinase (BTK). Two alternative synthetic routes for the simple preparation of desired compounds with variable substitutions at the N1, C4, C6 positions were introduced with readily available building blocks. Further, the developed synthetic approach was feasible for isomeric compounds bearing imidazo [4,5-b]pyridine scaffolds. In contrast to expectations based on previous studies, the imidazo [4,5-c]pyridine inhibitor exhibited a significantly higher activity against BTK compared to its imidazo [4,5-b]pyridine isomer. An inherent SAR study in the series of imidazo [4,5-c]pyridine compounds revealed a remarkably high tolerance of C6 substitutions for both hydrophobic and hydrophilic substituents. Preliminary cellular experiments indicated selective BTK targeting in Burkitt lymphoma and mantle cell lymphoma cell lines. The inhibitors could thus serve as starting points for further development, eventually leading to BTK inhibitors that could be used after ibrutinib failure.
Permanent Link: http://hdl.handle.net/11104/0322426