Bone-targeted Src kinase inhibitors: novel pyrrolo- and pyrazolopyrimidine analogues.
Src tyrosine kinase is a therapeutic target for bone diseases that has been validated by gene knockout studies. Furthermore, in vitro cellular studies implicate that Src has a positive regulatory role in osteoclasts and a negative regulatory role in osteoblasts. The potential use of Src inhibitors for osteoporosis therapy has been previously shown by novel bone-targeted ligands of the Src SH2 (e.g., AP22408) and non-bone-targeted, ATP-based inhibitors of Src kinase. Significant to this study, compounds 2-12 exemplify novel analogues of known pyrrolopyrimidine and pyrazolopyrimidine template-based Src kinase inhibitors that incorporate bone-targeting group modifications designed to provide tissue (bone) selectivity and diminished side effects. Accordingly, we report here the structure-based design, synthetic chemistry and biological testing of these compounds and proof-of-concept studies thereof.
Sundaramoorthi
Raji
R
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA. raji.sundaramoorthi@ariad.com
Shakespeare
William C
WC
Keenan
Terence P
TP
Metcalf
Chester A
CA
Wang
Yihan
Y
Mani
Ukti
U
Taylor
Merry
M
Liu
Shuangying
S
Bohacek
Regine S
RS
Narula
Surinder S
SS
Dalgarno
David C
DC
van Schravandijk
Marie Rose
MR
Violette
Sheila M
SM
Liou
Shuenn
S
Adams
Susan
S
Ram
Mary K
MK
Keats
Jeffrey A
JA
Weigle
Manfred
M
Sawyer
Tomi K
TK
Weigele
Manfred
M
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives*; D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010024:Osteoporosis / Q000188:drug therapy*; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D011687:Purines; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D019061:src-Family Kinases