title: Bone-targeted 2,6,9-trisubstituted purines: novel inhibitors of Src tyrosine kinase for the treatment of bone diseases.
abstract: Novel bone-targeted 2,6,9-trisubstituted purine template-based inhibitors of Src tyrosine kinase are described. Drug design studies of known purine compounds revealed that both positions-2 and -6 were suitable for incorporating bone-seeking moieties. A variety of bone-targeting groups with different affinity to hydroxyapatite were utilized in the study. Compound 3d was determined to be a potent Src inhibitor and was quite selective against a panel of other protein kinases.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA. yihan.wang@ariad.com
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wang
authors.forename: Chester A
authors.initials: CA
authors.lastname: Metcalf
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: Raji
authors.initials: R
authors.lastname: Sundaramoorthi
authors.forename: Terence P
authors.initials: TP
authors.lastname: Keenan
authors.forename: Regine S
authors.initials: RS
authors.lastname: Bohacek
authors.forename: Marie Rose
authors.initials: MR
authors.lastname: van Schravendijk
authors.forename: Shiela M
authors.initials: SM
authors.lastname: Violette
authors.forename: Surinder S
authors.initials: SS
authors.lastname: Narula
authors.forename: David C
authors.initials: DC
authors.lastname: Dalgarno
authors.forename: Chad
authors.initials: C
authors.lastname: Haraldson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Keats
authors.forename: Shuenn
authors.initials: S
authors.lastname: Liou
authors.forename: Ukti
authors.initials: U
authors.lastname: Mani
authors.forename: Selvi
authors.initials: S
authors.lastname: Pradeepan
authors.forename: Mary
authors.initials: M
authors.lastname: Ram
authors.forename: Susan
authors.initials: S
authors.lastname: Adams
authors.forename: Manfred
authors.initials: M
authors.lastname: Weigele
authors.forename: Tomi K
authors.initials: TK
authors.lastname: Sawyer
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy*; D016503:Drug Delivery Systems; D015195:Drug Design; D017886:Durapatite / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D011687:Purines; D000255:Adenosine Triphosphate; D017886:Durapatite; D019061:src-Family Kinases