title: Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors.
abstract: Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo.
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bardelle
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.forename: Nigel
authors.initials: N
authors.lastname: Brooks
authors.forename: Tanya
authors.initials: T
authors.lastname: Coleman
authors.forename: Darren
authors.initials: D
authors.lastname: Cross
authors.forename: Richard
authors.initials: R
authors.lastname: Ducray
authors.forename: Isabelle
authors.initials: I
authors.lastname: Green
authors.forename: Christine Lambert-van der
authors.initials: CL
authors.lastname: Brempt
authors.forename: Annie
authors.initials: A
authors.lastname: Olivier
authors.forename: Jon
authors.initials: J
authors.lastname: Read
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D036224:Receptor, EphB4; D019061:src-Family Kinases