Bone-targeted 2,6,9-trisubstituted purines: novel inhibitors of Src tyrosine kinase for the treatment of bone diseases.
Novel bone-targeted 2,6,9-trisubstituted purine template-based inhibitors of Src tyrosine kinase are described. Drug design studies of known purine compounds revealed that both positions-2 and -6 were suitable for incorporating bone-seeking moieties. A variety of bone-targeting groups with different affinity to hydroxyapatite were utilized in the study. Compound 3d was determined to be a potent Src inhibitor and was quite selective against a panel of other protein kinases.
Wang
Yihan
Y
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA. yihan.wang@ariad.com
Metcalf
Chester A
CA
Shakespeare
William C
WC
Sundaramoorthi
Raji
R
Keenan
Terence P
TP
Bohacek
Regine S
RS
van Schravendijk
Marie Rose
MR
Violette
Shiela M
SM
Narula
Surinder S
SS
Dalgarno
David C
DC
Haraldson
Chad
C
Keats
Jeffrey
J
Liou
Shuenn
S
Mani
Ukti
U
Pradeepan
Selvi
S
Ram
Mary
M
Adams
Susan
S
Weigele
Manfred
M
Sawyer
Tomi K
TK
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy*; D016503:Drug Delivery Systems; D015195:Drug Design; D017886:Durapatite / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D011687:Purines; D000255:Adenosine Triphosphate; D017886:Durapatite; D019061:src-Family Kinases