N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a Novel, Highly Selective, Orally …

LF Hennequin, J Allen, J Breed, J Curwen… - Journal of medicinal …, 2006 - ACS Publications
LF Hennequin, J Allen, J Breed, J Curwen, M Fennell, TP Green, C Lambert-van der Brempt…
Journal of medicinal chemistry, 2006ACS Publications
Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for
cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines
that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl
enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant
protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-
Chloro-1, 3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl) ethoxy]-5-(tetrahydro-2 H-pyran …
Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t1/2 = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.
ACS Publications