title: Bone-targeted pyrido[2,3-d]pyrimidin-7-ones: potent inhibitors of Src tyrosine kinase as novel antiresorptive agents.
abstract: 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.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA.
authors.forename: Chi B
authors.initials: CB
authors.lastname: Vu
authors.forename: George P
authors.initials: GP
authors.lastname: Luke
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kawahata
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wang
authors.forename: Raji
authors.initials: R
authors.lastname: Sundaramoorthi
authors.forename: Chester A
authors.initials: CA
authors.lastname: Metcalf
authors.forename: Terence P
authors.initials: TP
authors.lastname: Keenan
authors.forename: Selvi
authors.initials: S
authors.lastname: Pradeepan
authors.forename: Evelyn
authors.initials: E
authors.lastname: Corpuz
authors.forename: Taylor
authors.initials: T
authors.lastname: Merry
authors.forename: Regine S
authors.initials: RS
authors.lastname: Bohacek
authors.forename: David C
authors.initials: DC
authors.lastname: Dalgarno
authors.forename: Surinder S
authors.initials: SS
authors.lastname: Narula
authors.forename: Marie Rose
authors.initials: MR
authors.lastname: van Schravendijk
authors.forename: Mary K
authors.initials: MK
authors.lastname: Ram
authors.forename: Susan
authors.initials: S
authors.lastname: Adams
authors.forename: Shuenn
authors.initials: S
authors.lastname: Liou
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Keats
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.forename: Wei
authors.initials: W
authors.lastname: Guan
authors.forename: Manfred
authors.initials: M
authors.lastname: Weigele
authors.forename: Tomi K
authors.initials: TK
authors.lastname: Sawyer
mesh_terms: 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*
chemical_list: D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D017886:Durapatite; D019061:src-Family Kinases