title: 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.
abstract: 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.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA. william.shakespeare@ariad.com
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wang
authors.forename: Regine
authors.initials: R
authors.lastname: Bohacek
authors.forename: Terry
authors.initials: T
authors.lastname: Keenan
authors.forename: Raji
authors.initials: R
authors.lastname: Sundaramoorthi
authors.forename: Chet
authors.initials: C
authors.lastname: Metcalf
authors.forename: Anne
authors.initials: A
authors.lastname: Dilauro
authors.forename: Sonya
authors.initials: S
authors.lastname: Roeloffzen
authors.forename: Shuangying
authors.initials: S
authors.lastname: Liu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Saltmarsh
authors.forename: Guru
authors.initials: G
authors.lastname: Paramanathan
authors.forename: David
authors.initials: D
authors.lastname: Dalgarno
authors.forename: Surinder
authors.initials: S
authors.lastname: Narula
authors.forename: Selvi
authors.initials: S
authors.lastname: Pradeepan
authors.forename: Marie Rose
authors.initials: MR
authors.lastname: van Schravendijk
authors.forename: Jeff
authors.initials: J
authors.lastname: Keats
authors.forename: Mary
authors.initials: M
authors.lastname: Ram
authors.forename: Shuenn
authors.initials: S
authors.lastname: Liou
authors.forename: Susan
authors.initials: S
authors.lastname: Adams
authors.forename: Scott
authors.initials: S
authors.lastname: Wardwell
authors.forename: Julie
authors.initials: J
authors.lastname: Bogus
authors.forename: John
authors.initials: J
authors.lastname: Iuliucci
authors.forename: Manfred
authors.initials: M
authors.lastname: Weigele
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
authors.forename: Brendan
authors.initials: B
authors.lastname: Boyce
authors.forename: Tomi K
authors.initials: TK
authors.lastname: Sawyer
mesh_terms: 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
chemical_list: C511942:AP 23451; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D010281:Parathyroid Hormone; D010721:Phosphinic Acids; D011687:Purines; D019061:src-Family Kinases; D000225:Adenine