Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis

Autor:	Deodial Guiadeen, Shilan Liu, Jian Liu, Charles G. Garlisi, Arto D. Krikorian, Ronald M. Kim, Ying-Duo Gao, Peter Stivers, Hugh Y. Zhu, Alan B. Cooper, Rajan Anand, Philip E. Brandish, Younong Yu, Nathan Bays, Jiaqiang Cai, Ian Knemeyer, Erica Leccese, Zangwei Xu, Kevin M. Maloney, Alexandra Hicks, Sobhana Babu Boga, Chundao Yang, Joseph A. Kozlowski, My Sam Mansueto, Hao Wu, Thierry O. Fischmann, Desai Jagdish A, Jeremy Presland, Abdul-Basit Alhassan, Xiaolei Gao, Wang James J-S
Rok vydání:	2017
Předmět:	Models Molecular 0301 basic medicine Pyrazine Stereochemistry Morpholines Clinical Biochemistry hERG Pharmaceutical Science Biochemistry Arthritis Rheumatoid Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Transcriptional Regulator ERG hemic and lymphatic diseases Morpholine Drug Discovery Humans Bruton's tyrosine kinase Imidazole Protein Kinase Inhibitors Molecular Biology Dose-Response Relationship Drug Molecular Structure biology Kinase Organic Chemistry Imidazoles Protein-Tyrosine Kinases 030104 developmental biology chemistry 030220 oncology & carcinogenesis Leukocytes Mononuclear biology.protein Molecular Medicine Pharmacophore Tyrosine kinase
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 27:3939-3943
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2017.03.040
Popis:	8-Amino-imidazo[1,5- a ]pyrazine-based Bruton’s tyrosine kinase (BTK) inhibitors, such as 6 , exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6 . This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13 , 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::374dfa7e3c822671c1df7ad53a01c129 https://doi.org/10.1016/j.bmcl.2017.03.040 Zobrazit plný text záznamu Full Text from ScienceDirect