A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779
| Autor: | Matthew A. Curry, Zeqi Huang, Karen L. Milkiewicz, Benjamin J. Dugan, Pawel Dobrzanski, Bruce D. Dorsey, Eugen F. Mesaros, Bruce Ruggeri, Sheryl L. Meyer, Jennifer L. Mason, Mahfuza Jan, Mark S. Albom, Thelma S. Angeles, Diane E. Gingrich, Mark A. Ator, Allison L. Zulli, Lisa D. Aimone, Cynthia Serdikoff, Kevin J. Wells-Knecht |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Pyridines Administration Oral Biological Availability Mice Nude Antineoplastic Agents Pharmacology Crystallography X-Ray Cell Line Mice Structure-Activity Relationship Dogs hemic and lymphatic diseases Drug Discovery medicine Structure–activity relationship Moiety Potency Transferase Animals Humans Cell potency Janus kinase 2 biology Molecular Structure Chemistry Cancer Janus Kinase 2 Triazoles medicine.disease Xenograft Model Antitumor Assays Rats biology.protein Microsomes Liver Molecular Medicine Tyrosine kinase |
| Zdroj: | Journal of medicinal chemistry. 55(11) |
| ISSN: | 1520-4804 |
| Popis: | Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2. |
| Databáze: | OpenAIRE |
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