title: Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.
abstract: We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 02139, USA. mmweiss@amgen.com
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Polverino
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.forename: Loren
authors.initials: L
authors.lastname: Berry
authors.forename: Virginia
authors.initials: V
authors.lastname: Berry
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: 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: 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: 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*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2