Discovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton’s Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological Diseases
| Autor: | Dusica Cvetinovic Santos, Klaus Urbahns, Simone C. Zimmerli, Andreas Goutopoulos, Justin R. Potnick, Andrew Bender, Michael Meyring, Adam Shutes, Christopher Charles Victor Jones, Jared Head, Ben C. Askew, Bayard R. Huck, Ansgar Wegener, Hui Qiu, Theresa L. Johnson, Nadia Brugger, Sherer Brian A, Ngan Nguyen, Mohanraj Dhanabal, Ralf Schmidt, Roland Grenningloh, Reinaldo Jones, Richard D. Caldwell, Ariele Viacava Follis, Brian Healey, Montserrat Camps, Igor Mochalkin, Federica Morandi, Lesley Liu-Bujalski, Vikram Dutt, Brian L. Hodous, Anna Gardberg, Thomas Eichhorn |
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| Rok vydání: | 2019 |
| Předmět: |
Administration
Oral 01 natural sciences Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Piperidines In vivo Drug Discovery Agammaglobulinaemia Tyrosine Kinase medicine Humans Bruton's tyrosine kinase Epidermal growth factor receptor Protein Kinase Inhibitors B cell 030304 developmental biology 0303 health sciences Dose-Response Relationship Drug Molecular Structure biology Drug discovery Kinase 0104 chemical sciences 010404 medicinal & biomolecular chemistry Pyrimidines medicine.anatomical_structure Immune System Diseases chemistry Ibrutinib biology.protein Cancer research Molecular Medicine Tyrosine kinase |
| Zdroj: | Journal of Medicinal Chemistry. 62:7643-7655 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. |
| Databáze: | OpenAIRE |
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