Hit-to-lead optimization of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of KDR kinase inhibitors.
A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.
Dinges
Jürgen
J
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. dinges@abbott.com
Akritopoulou-Zanze
Irini
I
Arnold
Lee D
LD
Barlozzari
Teresa
T
Bousquet
Peter F
PF
Cunha
George A
GA
Ericsson
Anna M
AM
Iwasaki
Nobuhiko
N
Michaelides
Michael R
MR
Ogawa
Nobuo
N
Phelan
Kathleen M
KM
Rafferty
Paul
P
Sowin
Thomas J
TJ
Stewart
Kent D
KD
Tokuyama
Ryukou
R
Xia
Zhiren
Z
Zhang
Henry Q
HQ
D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D004487:Edema / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007192:Indenes / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry
D007192:Indenes; D011720:Pyrazoles; D042461:Vascular Endothelial Growth Factor A; C031280:pyrazole; D004958:Estradiol; D040301:Vascular Endothelial Growth Factor Receptor-2