7-Aminopyrazolo[1,5-a]pyrimidines as potent multitargeted receptor tyrosine kinase inhibitors.
7-Aminopyrazolo[1,5- a]pyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure-activity relationships of the pyrazolo[1,5- a]pyrimidine nucleus led to a series of 6-(4- N, N'-diphenyl)ureas that potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases. Several of these compounds, such as 34a, are potent inhibitors of kinase insert domain-containing receptor tyrosine kinase (KDR) both enzymatically (<10 nM) and cellularly (<10 nM). In addition, compound 34a possesses a favorable pharmacokinetic profile and demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model (ED 50 = 1.4 mg/kg).
Frey
Robin R
RR
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. robin.r.frey@abbott.com
Curtin
Michael L
ML
Albert
Daniel H
DH
Glaser
Keith B
KB
Pease
Lori J
LJ
Soni
Niru B
NB
Bouska
Jennifer J
JJ
Reuter
David
D
Stewart
Kent D
KD
Marcotte
Patrick
P
Bukofzer
Gail
G
Li
Junling
J
Davidsen
Steven K
SK
Michaelides
Michael R
MR
D000818:Animals; D004487:Edema / Q000188:drug therapy / Q000201:enzymology; D005260:Female; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry; D014591:Uterine Diseases / Q000188:drug therapy / Q000201:enzymology
D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D014508:Urea; D020794:Receptor Protein-Tyrosine Kinases