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J Med Chem. 2014 Jan 9;57(1):144-58. doi: 10.1021/jm401546n. Epub 2013 Dec 20.

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

Author information

1
AstraZeneca, Oncology Innovative Medicines, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.

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.

PMID:
24359159
DOI:
10.1021/jm401546n
[Indexed for MEDLINE]

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