Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors.
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.
Bardelle
Catherine
C
AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
Barlaam
Bernard
B
Brooks
Nigel
N
Coleman
Tanya
T
Cross
Darren
D
Ducray
Richard
R
Green
Isabelle
I
Brempt
Christine Lambert-van der
CL
Olivier
Annie
A
Read
Jon
J
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
D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D036224:Receptor, EphB4; D019061:src-Family Kinases