Download MendeleyDiscovery of 1-Methyl-1H-Imidazole Derivatives as Potent Jak2 Inhibitors.
Su, Q., Ioannidis, S., Chuaqui, C., Almeida, L., Alimzhanov, M., Bebernitz, G., Bell, K., Block, M., Howard, T., Huang, S., Huszar, D., Read, J.A., Rivard Costa, C., Shi, J., Su, M., Ye, M., Zinda, M.(2014) J Med Chem 57: 144
- PubMed: 24359159
- DOI: https://doi.org/10.1021/jm401546n
- Primary Citation of Related Structures:
4C61, 4C62 - PubMed Abstract:
Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.
Organizational Affiliation:
AstraZeneca, Oncology Innovative Medicines, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
