Synthesis and SAR of 1-acetanilide-4-aminopyrazole-substituted quinazolines: selective inhibitors of Aurora B kinase with potent anti-tumor activity.
A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume.
Foote
Kevin M
KM
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. kevin.foote@astrazeneca.com
Mortlock
Andrew A
AA
Heron
Nicola M
NM
Jung
Frédéric H
FH
Hill
George B
GB
Pasquet
Georges
G
Brady
Madeleine C
MC
Green
Stephen
S
Heaton
Simon P
SP
Kearney
Sarah
S
Keen
Nicholas J
NJ
Odedra
Rajesh
R
Wedge
Stephen R
SR
Wilkinson
Robert W
RW
D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D051638:Ether-A-Go-Go Potassium Channels; D006657:Histones; C496884:KCNH1 protein, human; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases