Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase.
The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.
Mortlock
Andrew A
AA
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Foote
Kevin M
KM
Heron
Nicola M
NM
Jung
Frédéric H
FH
Pasquet
Georges
G
Lohmann
Jean-Jacques M
JJ
Warin
Nicolas
N
Renaud
Fabrice
F
De Savi
Chris
C
Roberts
Nicola J
NJ
Johnson
Trevor
T
Dousson
Cyril B
CB
Hill
George B
GB
Perkins
David
D
Hatter
Glenn
G
Wilkinson
Robert W
RW
Wedge
Stephen R
SR
Heaton
Simon P
SP
Odedra
Rajesh
R
Keen
Nicholas J
NJ
Crafter
Claire
C
Brown
Elaine
E
Thompson
Katherine
K
Brightwell
Stephen
S
Khatri
Liz
L
Brady
Madeleine C
MC
Kearney
Sarah
S
McKillop
David
D
Rhead
Steve
S
Parry
Tony
T
Green
Stephen
S
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors; D004354:Drug Screening Assays, Antitumor; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010755:Organophosphates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006657:Histones; D010755:Organophosphates; D011355:Prodrugs; D011720:Pyrazoles; D011799:Quinazolines; D011994:Recombinant Proteins; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576920:Aurka protein, rat; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases