title: 2,7-Pyrrolo[2,1-f][1,2,4]triazines as JAK2 inhibitors: modification of target structure to minimize reactive metabolite formation.
abstract: The JAK2/STAT pathway has important roles in hematopoiesis. With the discovery of the JAK2 V617F mutation and its presence in many patients with myeloproliferative neoplasms, research in the JAK2 inhibitor arena has dramatically increased. We report a novel series of potent JAK2 inhibitors containing a 2,7-pyrrolotriazine core. To minimize potential drug-induced toxicity, targets were analyzed for the ability to form a glutathione adduct. Glutathione adduct formation was decreased by modification of the aniline substituent at C2.
authors: Worldwide Discovery Research, Cephalon, Inc. 145 Brandywine Parkway, West Chester, PA 19380-4245, USA. lweinber3@yahoo.com
authors: Linda R
authors: LR
authors: Weinberg
authors: Mark S
authors: MS
authors: Albom
authors: Thelma S
authors: TS
authors: Angeles
authors: Henry J
authors: HJ
authors: Breslin
authors: Diane E
authors: DE
authors: Gingrich
authors: Zeqi
authors: Z
authors: Huang
authors: Joseph G
authors: JG
authors: Lisko
authors: Jennifer L
authors: JL
authors: Mason
authors: Karen L
authors: KL
authors: Milkiewicz
authors: Tho V
authors: TV
authors: Thieu
authors: Ted L
authors: TL
authors: Underiner
authors: Gregory J
authors: GJ
authors: Wells
authors: Kevin J
authors: KJ
authors: Wells-Knecht
authors: Bruce D
authors: BD
authors: Dorsey
mesh_terms: D019943:Amino Acid Substitution; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014227:Triazines; C093444:1,2,4-triazine; D053614:Janus Kinase 2; D005978:Glutathione