title: Bone-targeted Src kinase inhibitors: novel pyrrolo- and pyrazolopyrimidine analogues.
abstract: 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.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA. raji.sundaramoorthi@ariad.com
authors.forename: Raji
authors.initials: R
authors.lastname: Sundaramoorthi
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: Terence P
authors.initials: TP
authors.lastname: Keenan
authors.forename: Chester A
authors.initials: CA
authors.lastname: Metcalf
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wang
authors.forename: Ukti
authors.initials: U
authors.lastname: Mani
authors.forename: Merry
authors.initials: M
authors.lastname: Taylor
authors.forename: Shuangying
authors.initials: S
authors.lastname: Liu
authors.forename: Regine S
authors.initials: RS
authors.lastname: Bohacek
authors.forename: Surinder S
authors.initials: SS
authors.lastname: Narula
authors.forename: David C
authors.initials: DC
authors.lastname: Dalgarno
authors.forename: Marie Rose
authors.initials: MR
authors.lastname: van Schravandijk
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Violette
authors.forename: Shuenn
authors.initials: S
authors.lastname: Liou
authors.forename: Susan
authors.initials: S
authors.lastname: Adams
authors.forename: Mary K
authors.initials: MK
authors.lastname: Ram
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Keats
authors.forename: Manfred
authors.initials: M
authors.lastname: Weigle
authors.forename: Tomi K
authors.initials: TK
authors.lastname: Sawyer
authors.forename: Manfred
authors.initials: M
authors.lastname: Weigele
mesh_terms: 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*
chemical_list: D004791:Enzyme Inhibitors; D011687:Purines; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D019061:src-Family Kinases