Novel N9-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors.
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.
Wang
Yihan
Y
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA.
Shakespeare
William C
WC
Huang
Wei-Sheng
WS
Sundaramoorthi
Raji
R
Lentini
Scott
S
Das
Sasmita
S
Liu
Shuangying
S
Banda
Geeta
G
Wen
David
D
Zhu
Xiaotian
X
Xu
Qihong
Q
Keats
Jeffrey
J
Wang
Frank
F
Wardwell
Scott
S
Ning
Yaoyu
Y
Snodgrass
Joseph T
JT
Broudy
Mark I
MI
Russian
Karin
K
Dalgarno
David
D
Clackson
Tim
T
Sawyer
Tomi K
TK
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*
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases