title: Discovery of 1-methyl-1H-imidazole derivatives as potent Jak2 inhibitors.
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.
authors.affiliation: AstraZeneca, Oncology Innovative Medicines, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Qibin
authors.initials: Q
authors.lastname: Su
authors.forename: Stephanos
authors.initials: S
authors.lastname: Ioannidis
authors.forename: Claudio
authors.initials: C
authors.lastname: Chuaqui
authors.forename: Lynsie
authors.initials: L
authors.lastname: Almeida
authors.forename: Marat
authors.initials: M
authors.lastname: Alimzhanov
authors.forename: Geraldine
authors.initials: G
authors.lastname: Bebernitz
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bell
authors.forename: Michael
authors.initials: M
authors.lastname: Block
authors.forename: Tina
authors.initials: T
authors.lastname: Howard
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.forename: Jon A
authors.initials: JA
authors.lastname: Read
authors.forename: Caroline
authors.initials: C
authors.lastname: Rivard Costa
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.forename: Mei
authors.initials: M
authors.lastname: Su
authors.forename: Minwei
authors.initials: M
authors.lastname: Ye
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2