title: SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.
abstract: We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.
authors.affiliation: Exelixis, Department of Drug Discovery, 169 Harbor Way, South San Francisco, CA 94083, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Forsyth
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Kearney
authors.forename: Byung Gyu
authors.initials: BG
authors.lastname: Kim
authors.forename: Henry W B
authors.initials: HW
authors.lastname: Johnson
authors.forename: Naing
authors.initials: N
authors.lastname: Aay
authors.forename: Arlyn
authors.initials: A
authors.lastname: Arcalas
authors.forename: David S
authors.initials: DS
authors.lastname: Brown
authors.forename: Vicky
authors.initials: V
authors.lastname: Chan
authors.forename: Jeff
authors.initials: J
authors.lastname: Chen
authors.forename: Hongwang
authors.initials: H
authors.lastname: Du
authors.forename: Sergey
authors.initials: S
authors.lastname: Epshteyn
authors.forename: Adam A
authors.initials: AA
authors.lastname: Galan
authors.forename: Tai P
authors.initials: TP
authors.lastname: Huynh
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ibrahim
authors.forename: Brian
authors.initials: B
authors.lastname: Kane
authors.forename: Elena S
authors.initials: ES
authors.lastname: Koltun
authors.forename: Grace
authors.initials: G
authors.lastname: Mann
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Meyr
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Lee
authors.forename: Gary L
authors.initials: GL
authors.lastname: Lewis
authors.forename: Robin T
authors.initials: RT
authors.lastname: Noguchi
authors.forename: Michael
authors.initials: M
authors.lastname: Pack
authors.forename: Brian H
authors.initials: BH
authors.lastname: Ridgway
authors.forename: Xian
authors.initials: X
authors.lastname: Shi
authors.forename: Craig S
authors.initials: CS
authors.lastname: Takeuchi
authors.forename: Peiwen
authors.initials: P
authors.lastname: Zu
authors.forename: James W
authors.initials: JW
authors.lastname: Leahy
authors.forename: John M
authors.initials: JM
authors.lastname: Nuss
authors.forename: Ron
authors.initials: R
authors.lastname: Aoyama
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.forename: Steven B
authors.initials: SB
authors.lastname: Gendreau
authors.forename: Robert
authors.initials: R
authors.lastname: Kassees
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Shwu-Hwa
authors.initials: SH
authors.lastname: Lin
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Martini
authors.forename: Thomas
authors.initials: T
authors.lastname: Stout
authors.forename: Philip
authors.initials: P
authors.lastname: Tong
authors.forename: John
authors.initials: J
authors.lastname: Woolfrey
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D057166:High-Throughput Screening Assays; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C587876:XL019 compound; D011392:Proline; D053614:Janus Kinase 2