title: Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation.
abstract: A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 02139, USA. harmange@amgen.com
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Julie
authors.initials: J
authors.lastname: Germain
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Polverino
authors.forename: George
authors.initials: G
authors.lastname: Borg
authors.forename: James
authors.initials: J
authors.lastname: Bready
authors.forename: Danlin
authors.initials: D
authors.lastname: Chen
authors.forename: Deborah
authors.initials: D
authors.lastname: Choquette
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Tom
authors.initials: T
authors.lastname: DeMelfi
authors.forename: Lucian
authors.initials: L
authors.lastname: DiPietro
authors.forename: Nicholas
authors.initials: N
authors.lastname: Doerr
authors.forename: Juan
authors.initials: J
authors.lastname: Estrada
authors.forename: Julie
authors.initials: J
authors.lastname: Flynn
authors.forename: Russell F
authors.initials: RF
authors.lastname: Graceffa
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Harriman
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaufman
authors.forename: Daniel S
authors.initials: DS
authors.lastname: La
authors.forename: Alexander
authors.initials: A
authors.lastname: Long
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Martin
authors.forename: Sesha
authors.initials: S
authors.lastname: Neervannan
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Michele
authors.initials: M
authors.lastname: Potashman
authors.forename: Kelly
authors.initials: K
authors.lastname: Regal
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Roveto
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schrag
authors.forename: Charlie
authors.initials: C
authors.lastname: Starnes
authors.forename: Andrew
authors.initials: A
authors.lastname: Tasker
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Ryan D
authors.initials: RD
authors.lastname: White
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Roger
authors.initials: R
authors.lastname: Zanon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016510:Corneal Neovascularization / Q000097:blood; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor