title: Novel N9-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors.
abstract: Novel N(9)-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described. The key structural feature is a trans vinyl linkage at N(9) on the purine core which projects hydrophobic substituents into the selectivity pocket at the rear of the ATP site. Their synthesis was achieved through a Horner-Wadsworth-Emmons reaction of N(9)-phosphorylmethylpurines and substituted benzaldehydes or Heck reactions between 9-vinyl purines and aryl halides. Most compounds are potent inhibitors of both Src and Abl kinase, and several possess good oral bioavailability.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wang
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Huang
authors.forename: Raji
authors.initials: R
authors.lastname: Sundaramoorthi
authors.forename: Scott
authors.initials: S
authors.lastname: Lentini
authors.forename: Sasmita
authors.initials: S
authors.lastname: Das
authors.forename: Shuangying
authors.initials: S
authors.lastname: Liu
authors.forename: Geeta
authors.initials: G
authors.lastname: Banda
authors.forename: David
authors.initials: D
authors.lastname: Wen
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhu
authors.forename: Qihong
authors.initials: Q
authors.lastname: Xu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Keats
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.forename: Scott
authors.initials: S
authors.lastname: Wardwell
authors.forename: Yaoyu
authors.initials: Y
authors.lastname: Ning
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Snodgrass
authors.forename: Mark I
authors.initials: MI
authors.lastname: Broudy
authors.forename: Karin
authors.initials: K
authors.lastname: Russian
authors.forename: David
authors.initials: D
authors.lastname: Dalgarno
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.forename: Tomi K
authors.initials: TK
authors.lastname: Sawyer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000502:physiology; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases