title: Hit-to-lead optimization of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of KDR kinase inhibitors.
abstract: 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.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. dinges@abbott.com
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dinges
authors.forename: Irini
authors.initials: I
authors.lastname: Akritopoulou-Zanze
authors.forename: Lee D
authors.initials: LD
authors.lastname: Arnold
authors.forename: Teresa
authors.initials: T
authors.lastname: Barlozzari
authors.forename: Peter F
authors.initials: PF
authors.lastname: Bousquet
authors.forename: George A
authors.initials: GA
authors.lastname: Cunha
authors.forename: Anna M
authors.initials: AM
authors.lastname: Ericsson
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Iwasaki
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ogawa
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Phelan
authors.forename: Paul
authors.initials: P
authors.lastname: Rafferty
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sowin
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Ryukou
authors.initials: R
authors.lastname: Tokuyama
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Xia
authors.forename: Henry Q
authors.initials: HQ
authors.lastname: Zhang
mesh_terms: 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
chemical_list: D007192:Indenes; D011720:Pyrazoles; D042461:Vascular Endothelial Growth Factor A; C031280:pyrazole; D004958:Estradiol; D040301:Vascular Endothelial Growth Factor Receptor-2