Discovery of 1‑Methyl‑1H‑imidazole Derivatives as Potent Jak2 Inhibitors

• Published in: Journal of medicinal chemistry Vol. 57; no. 1; pp. 144 - 158
• Main Authors: Su, Qibin, Ioannidis, Stephanos, Chuaqui, Claudio, Almeida, Lynsie, Alimzhanov, Marat, Bebernitz, Geraldine, Bell, Kirsten, Block, Michael, Howard, Tina, Huang, Shan, Huszar, Dennis, Read, Jon A, Rivard Costa, Caroline, Shi, Jie, Su, Mei, Ye, Minwei, Zinda, Michael
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.01.2014; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Chemistry, Medicinal; Dogs; Drug Discovery; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Janus Kinase 2 - antagonists & inhibitors; Life Sciences & Biomedicine; Mice; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; Xenograft Model Antitumor Assays; SURVIVAL; MUTATION; TYROSINE KINASE JAK2; AZD1480; THROMBOCYTHEMIA; IDENTIFICATION; CANCER
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401546n

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.