• J. Med. Chem. · Jan 2014

    Discovery of 1-methyl-1H-imidazole derivatives as potent Jak2 inhibitors.

    • Qibin Su, Stephanos Ioannidis, Claudio Chuaqui, Lynsie Almeida, Marat Alimzhanov, Geraldine Bebernitz, Kirsten Bell, Michael Block, Tina Howard, Shan Huang, Dennis Huszar, Jon A Read, Caroline Rivard Costa, Jie Shi, Mei Su, Minwei Ye, and Michael Zinda.
    • AstraZeneca, Oncology Innovative Medicines, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
    • J. Med. Chem. 2014 Jan 9; 57 (1): 144-58.

    AbstractStructure 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.

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