1,4,6-Trisubstituted imidazo[4,5-c]pyridines as inhibitors of Bruton's tyrosine kinase
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
33340912
DOI
10.1016/j.ejmech.2020.113094
PII: S0223-5234(20)31066-7
Knihovny.cz E-zdroje
- Klíčová slova
- Bruton’s tyrosine kinase, Inhibitor, Protein kinase, imidazo[4,5-c]pyridine,
- MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- lidé MeSH
- nehodgkinský lymfom farmakoterapie MeSH
- proteinkinasa BTK antagonisté a inhibitory MeSH
- pyridiny farmakologie terapeutické užití MeSH
- signální transdukce MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- inhibitory proteinkinas MeSH
- proteinkinasa BTK MeSH
- pyridiny MeSH
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.
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