title: 2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors.
abstract: A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.
authors.affiliation: Ligand Pharmaceuticals, Inc, Cranbury, NJ 08512, USA. acole@ligand.com
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cole
authors.forename: Adolph C
authors.initials: AC
authors.lastname: Bohnstedt
authors.forename: Vidyadhar
authors.initials: V
authors.lastname: Paradkar
authors.forename: Celia
authors.initials: C
authors.lastname: Kingsbury
authors.forename: Jorge G
authors.initials: JG
authors.lastname: Quintero
authors.forename: Haengsoon
authors.initials: H
authors.lastname: Park
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Lu
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.forename: Irina
authors.initials: I
authors.lastname: Neagu
authors.forename: David J
authors.initials: DJ
authors.lastname: Diller
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Letourneau
authors.forename: Yuefei
authors.initials: Y
authors.lastname: Shao
authors.forename: Ray A
authors.initials: RA
authors.lastname: James
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Riviello
authors.forename: Koc-Kan
authors.initials: KK
authors.lastname: Ho
authors.forename: Tsung H
authors.initials: TH
authors.lastname: Lin
authors.forename: Bojing
authors.initials: B
authors.lastname: Wang
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Appell
authors.forename: Matthew
authors.initials: M
authors.lastname: Sills
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Quadros
authors.forename: Earl F
authors.initials: EF
authors.lastname: Kimble
authors.forename: Michael H J
authors.initials: MH
authors.lastname: Ohlmeyer
authors.forename: Maria L
authors.initials: ML
authors.lastname: Webb
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D051379:Mice; D023421:Models, Animal; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011687:Purines; D007371:Interferon-gamma; D053616:Janus Kinase 3