Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases.
In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6100, USA. mike.curtin@abbott.com
Michael L
ML
Curtin
H Robin
HR
Heyman
Robin R
RR
Frey
Patrick A
PA
Marcotte
Keith B
KB
Glaser
James R
JR
Jankowski
Terrance J
TJ
Magoc
Daniel H
DH
Albert
Amanda M
AM
Olson
David R
DR
Reuter
Jennifer J
JJ
Bouska
Debra A
DA
Montgomery
Joann P
JP
Palma
Cherrie K
CK
Donawho
Kent D
KD
Stewart
Chris
C
Tse
Michael R
MR
Michaelides
D000586:Amination; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C031280:pyrazole; D040301:Vascular Endothelial Growth Factor Receptor-2; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases