title: Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase.
abstract: 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.
authors: AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Andrew A
authors: AA
authors: Mortlock
authors: Kevin M
authors: KM
authors: Foote
authors: Nicola M
authors: NM
authors: Heron
authors: Frédéric H
authors: FH
authors: Jung
authors: Georges
authors: G
authors: Pasquet
authors: Jean-Jacques M
authors: JJ
authors: Lohmann
authors: Nicolas
authors: N
authors: Warin
authors: Fabrice
authors: F
authors: Renaud
authors: Chris
authors: C
authors: De Savi
authors: Nicola J
authors: NJ
authors: Roberts
authors: Trevor
authors: T
authors: Johnson
authors: Cyril B
authors: CB
authors: Dousson
authors: George B
authors: GB
authors: Hill
authors: David
authors: D
authors: Perkins
authors: Glenn
authors: G
authors: Hatter
authors: Robert W
authors: RW
authors: Wilkinson
authors: Stephen R
authors: SR
authors: Wedge
authors: Simon P
authors: SP
authors: Heaton
authors: Rajesh
authors: R
authors: Odedra
authors: Nicholas J
authors: NJ
authors: Keen
authors: Claire
authors: C
authors: Crafter
authors: Elaine
authors: E
authors: Brown
authors: Katherine
authors: K
authors: Thompson
authors: Stephen
authors: S
authors: Brightwell
authors: Liz
authors: L
authors: Khatri
authors: Madeleine C
authors: MC
authors: Brady
authors: Sarah
authors: S
authors: Kearney
authors: David
authors: D
authors: McKillop
authors: Steve
authors: S
authors: Rhead
authors: Tony
authors: T
authors: Parry
authors: Stephen
authors: S
authors: Green
mesh_terms: 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
chemical_list: 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