Structure–activity relationship studies of imidazo[1,2-c]pyrimidine derivatives as potent and orally effective Syk family kinases inhibitors
| Autor: | Hiroaki Kobayashi, Motoyasu Ozawa, Harunobu Mukaiyama, Akihito Hirabayashi, Satoko Nakayama, Hiroaki Shiohara, Keiko Misawa, Eiichi Tsuji, Keiji Miyazawa, Masayuki Isaji, Hideki Ohnota |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Clinical Biochemistry Administration Oral Pharmaceutical Science Syk chemical and pharmacologic phenomena Pharmacology Crystallography X-Ray Biochemistry Inhibitory Concentration 50 Mice Structure-Activity Relationship Drug Discovery Animals Humans Syk Kinase Structure–activity relationship Protein kinase A Protein Kinase Inhibitors Molecular Biology chemistry.chemical_classification Mice Inbred ICR ZAP-70 Protein-Tyrosine Kinase Molecular Structure biology Kinase Chemistry Organic Chemistry Imidazoles Intracellular Signaling Peptides and Proteins hemic and immune systems Protein-Tyrosine Kinases Enzyme Activation Pyrimidines Enzyme Enzyme inhibitor biology.protein Molecular Medicine Signal transduction Tyrosine kinase |
| Zdroj: | Bioorganic & Medicinal Chemistry. 16:9247-9260 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2008.09.015 |
| Popis: | Spleen tyrosine kinase (Syk) and zeta-associated protein kinase of 70 kDa (ZAP-70) are members of the Syk family and non-receptor-type protein tyrosine kinases, which play crucial roles in B- and T-cell activation. Therefore, a Syk family tyrosine kinases inhibitor would be a useful therapeutic agent for the treatment of various allergic disorders and autoimmune diseases. Previously, we reported that 1,2,4-triazolo[4,3-c]pyrimidine derivative 1 and 1,2,4-triazolo[1,5-c]pyrimidine derivative 2 showed strong inhibitory activities against Syk family kinases. These compounds also exhibited high-level suppression of IL-2 in cellular assays. However, their oral efficacies were poor in a mouse model of IL-2 production. To improve oral effectiveness, we investigated a new series of Syk family kinases inhibitors. We found that imidazo[1,2-c]pyrimidine derivatives potently inhibited the Syk family kinases. Among these agents, compound 9f not only showed strong inhibitory activities against Syk and ZAP-70 kinases in vitro, but its oral administration resulted in the in vivo suppression of both the passive cutaneous anaphylaxis reaction and Concanavalin A-induced IL-2 production in a mouse model. |
| Databáze: | OpenAIRE |
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