SAR of carbon-linked, 2-substituted purines: synthesis and characterization of AP23451 as a novel bone-targeted inhibitor of Src tyrosine kinase with in vivo anti-resorptive activity.
Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Here, we describe structure activity relationships of a novel series of carbon-linked, 2-substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo. AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone-targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface. AP23451 exhibited an IC50 = 68 nm against Src kinase; an X-ray crystal structure of the molecule complexed with Src detailed the molecular interactions responsible for its Src inhibition. In vivo, AP23451 demonstrated a dose-dependent decrease in PTH-induced hypercalcemia. Moreover, AP23517, a structurally and biochemically similar molecule with comparable activity (IC50 = 73 nm) except devoid of the bone-targeting element, demonstrated significantly reduced in vivo efficacy, suggesting that Src activity was necessary but not sufficient for in vivo activity in this series of compounds.
Shakespeare
William C
WC
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA. william.shakespeare@ariad.com
Wang
Yihan
Y
Bohacek
Regine
R
Keenan
Terry
T
Sundaramoorthi
Raji
R
Metcalf
Chet
C
Dilauro
Anne
A
Roeloffzen
Sonya
S
Liu
Shuangying
S
Saltmarsh
Jennifer
J
Paramanathan
Guru
G
Dalgarno
David
D
Narula
Surinder
S
Pradeepan
Selvi
S
van Schravendijk
Marie Rose
MR
Keats
Jeff
J
Ram
Mary
M
Liou
Shuenn
S
Adams
Susan
S
Wardwell
Scott
S
Bogus
Julie
J
Iuliucci
John
J
Weigele
Manfred
M
Xing
Lianping
L
Boyce
Brendan
B
Sawyer
Tomi K
TK
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy*; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006934:Hypercalcemia; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D010024:Osteoporosis / Q000188:drug therapy; D010281:Parathyroid Hormone / Q000494:pharmacology; D010721:Phosphinic Acids; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
C511942:AP 23451; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D010281:Parathyroid Hormone; D010721:Phosphinic Acids; D011687:Purines; D019061:src-Family Kinases; D000225:Adenine