title: Imidazo[1,2-a]pyrazine diaryl ureas: inhibitors of the receptor tyrosine kinase EphB4.
abstract: Inhibition of receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs) has been validated by recently launched small molecules Sutent and Nexavar, both of which display activities against several angiogenesis-related RTKs. EphB4, a receptor tyrosine kinase (RTK) involved in the processes of embryogenesis and angiogenesis, has been shown to be aberrantly up regulated in many cancer types such as breast, lung, bladder and prostate. We propose that inhibition of EphB4 in addition to other validated RTKs would enhance the anti-angiogenic effect and ultimately result in more pronounced anti-cancer efficacy. Herein we report the discovery and SAR of a novel series of imidazo[1,2-a]pyrazine diarylureas that show nanomolar potency for the EphB4 receptor, in addition to potent activity against several other RTKs.
authors.affiliation: Department of Medicinal Chemistry, CGI Pharmaceuticals, Inc., 36 East Industrial Road, Branford, CT 06405, USA. smitchell@cgipharma.com
authors.forename: Scott A
authors.initials: SA
authors.lastname: Mitchell
authors.forename: Mihaela Diana
authors.initials: MD
authors.lastname: Danca
authors.forename: Peter A
authors.initials: PA
authors.lastname: Blomgren
authors.forename: James W
authors.initials: JW
authors.lastname: Darrow
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Currie
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Kropf
authors.forename: Seung H
authors.initials: SH
authors.lastname: Lee
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gallion
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Xiong
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Pippin
authors.forename: Robert W
authors.initials: RW
authors.lastname: DeSimone
authors.forename: David R
authors.initials: DR
authors.lastname: Brittelli
authors.forename: David C
authors.initials: DC
authors.lastname: Eustice
authors.forename: Aaron
authors.initials: A
authors.lastname: Bourret
authors.forename: Melissa
authors.initials: M
authors.lastname: Hill-Drzewi
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Maciejewski
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Elkin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives*
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D014508:Urea; D036224:Receptor, EphB4