Discovery of a novel series of pyridine and pyrimidine carboxamides as potent and selective covalent inhibitors of Btk

Autor:	Constantin Neagu, Johnson Theresa L, Federica Morandi, Sherer Brian A, Roland Grenningloh, Jared Head, Reinaldo Jones, Hui Qiu, Andreas Goutopoulos, Anna Gardberg, Lesley Liu-Bujalski, Igor Mochalkin, Ariele Viacava Follis, Richard D. Caldwell
Rok vydání:	2018
Předmět:	0301 basic medicine Pyrimidine Pyridines Clinical Biochemistry Administration Oral Pharmaceutical Science Biochemistry Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Piperidines immune system diseases Murine lupus hemic and lymphatic diseases Drug Discovery Pyridine Agammaglobulinaemia Tyrosine Kinase Animals Humans Bruton's tyrosine kinase Protein Kinase Inhibitors Molecular Biology chemistry.chemical_classification Molecular Structure biology Adenine Organic Chemistry Pyrimidines 030104 developmental biology Enzyme chemistry Covalent bond 030220 oncology & carcinogenesis Ibrutinib biology.protein Cancer research Pyrazoles Molecular Medicine Structure based Caco-2 Cells
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 28:3419-3424
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2018.09.033
Popis:	Btk is an attractive target for the treatment of a range of Bcell malignancies as well as several autoimmune diseases such as murine lupus and rheumatoid arthritis. Several covalent irreversible inhibitors of Btk are currently in development including ibrutinib which was approved for treatment of B-cell malignancies. Herein, we describe our efforts using X-ray guided structure based design (SBD) to identify a novel chemical series of covalent Btk inhibitors. The resulting pyridine carboxamides were potent and selective inhibitors of Btk having excellent enzymatic and cellular inhibitory activity.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ea41e0e5e139c277b6c3ead12456930b https://doi.org/10.1016/j.bmcl.2018.09.033 Zobrazit plný text záznamu Full Text from ScienceDirect