Bone-targeted pyrido[2,3-d]pyrimidin-7-ones: potent inhibitors of Src tyrosine kinase as novel antiresorptive agents.
The design of bone-targeted pyrido[2,3-d]pyrimidin-7-ones as Src tyrosine kinase inhibitors is described. Leveraging SAR from known compounds and using structure-based methods, we were able to rapidly incorporate bone binding components, which maintained, and even increased potency against the target enzyme. Compound 4 displayed a high affinity for hydroxyapatite, a major constituent of bone, and demonstrated antiresoprtive activity in our cell-based assay.
Vu
Chi B
CB
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA.
Luke
George P
GP
Kawahata
Noriyuki
N
Shakespeare
William C
WC
Wang
Yihan
Y
Sundaramoorthi
Raji
R
Metcalf
Chester A
CA
Keenan
Terence P
TP
Pradeepan
Selvi
S
Corpuz
Evelyn
E
Merry
Taylor
T
Bohacek
Regine S
RS
Dalgarno
David C
DC
Narula
Surinder S
SS
van Schravendijk
Marie Rose
MR
Ram
Mary K
MK
Adams
Susan
S
Liou
Shuenn
S
Keats
Jeffrey A
JA
Violette
Shelia M
SM
Guan
Wei
W
Weigele
Manfred
M
Sawyer
Tomi K
TK
D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy*; D001862:Bone Resorption / Q000188:drug therapy / Q000517:prevention & control*; D003198:Computer Simulation; D003804:Dentin / Q000378:metabolism; D015195:Drug Design; D017886:Durapatite / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010010:Osteoclasts / Q000187:drug effects; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D017886:Durapatite; D019061:src-Family Kinases