Optimization of a novel piperazinone series as potent selective peripheral covalent BTK inhibitors
| Autor: | Bin Ma, Claire M. Metrick, Chungang Gu, Marc Hoemberger, Bekim Bajrami, Eris Bame, Jiansheng Huang, Michael Mingueneau, Paramasivam Murugan, Joseph C. Santoro, Hao Tang, Ti Wang, Brian T. Hopkins |
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| Rok vydání: | 2021 |
| Předmět: |
B-Lymphocytes
Dose-Response Relationship Drug Molecular Structure Organic Chemistry Clinical Biochemistry Pharmaceutical Science Biochemistry Piperazines Structure-Activity Relationship Drug Discovery Agammaglobulinaemia Tyrosine Kinase Molecular Medicine Humans Molecular Biology Protein Kinase Inhibitors Cell Proliferation |
| Zdroj: | Bioorganicmedicinal chemistry letters. 60 |
| ISSN: | 1464-3405 |
| Popis: | BTK is a tyrosine kinase playing an important role in B cell and myeloid cell functions through B cell receptor (BCR) signaling and Fc receptor (FcR) signaling. Selective inhibition of BTK has the potential to provide therapeutical benefits to patients suffering from autoimmune diseases. Here we report the design, optimization, and characterization of novel potent and highly selective covalent BTK inhibitors. Starting from a piperazinone hit derived from a selective reversible inhibitor, we solved the whole blood cellular potency issue by introducing an electrophilic warhead to reach Cys481. This design led to a covalent irreversible BTK inhibitor series with excellent kinase selectivity as well as good whole blood CD69 cellular potency. Optimization of metabolic stability led to representative compounds like 42, which demonstrated strong cellular target occupancy and inhibition of B-cell proliferation measured by proximal and distal functional activity. |
| Databáze: | OpenAIRE |
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