title: (6,7-Dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines: platelet-derived growth factor receptor tyrosine kinase inhibitors with broad antiproliferative activity against tumor cells.
abstract: A series of (6,7-dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines has been optimized to preserve both potent kinase inhibition activity against the angiogenesis target, the receptor tyrosine kinase of Platelet-Derived Growth Factor-BB (PDGF-BB), and to improve the broad tumor cell antiproliferative activity of these compounds. This series culminates in the discovery of 17 (JNJ-10198409), a compound with anti-PDGFR-beta kinase activity (IC(50)=0.0042 microM) and potent antiproliferative activity in six of eight human tumor cell lines (IC(50) < 0.033 microM).
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Spring House Research and Early Development Site, Spring House, Pennsylvania 19477, USA.
authors.forename: Chih Y
authors.initials: CY
authors.lastname: Ho
authors.forename: Donald W
authors.initials: DW
authors.lastname: Ludovici
authors.forename: Umar S M
authors.initials: US
authors.lastname: Maharoof
authors.forename: Jay
authors.initials: J
authors.lastname: Mei
authors.forename: Jan L
authors.initials: JL
authors.lastname: Sechler
authors.forename: Robert W
authors.initials: RW
authors.lastname: Tuman
authors.forename: Eric D
authors.initials: ED
authors.lastname: Strobel
authors.forename: Laura
authors.initials: L
authors.lastname: Andraka
authors.forename: Hwa-Kwo
authors.initials: HK
authors.lastname: Yen
authors.forename: Gregory
authors.initials: G
authors.lastname: Leo
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Harold
authors.initials: H
authors.lastname: Almond
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Ann
authors.initials: A
authors.lastname: DeVine
authors.forename: Rose M
authors.initials: RM
authors.lastname: Tominovich
authors.forename: Judith
authors.initials: J
authors.lastname: Baker
authors.forename: Stuart
authors.initials: S
authors.lastname: Emanuel
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gruninger
authors.forename: Steven A
authors.initials: SA
authors.lastname: Middleton
authors.forename: Dana L
authors.initials: DL
authors.lastname: Johnson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000077214:Becaplermin; D002460:Cell Line; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020574:Proto-Oncogene Proteins c-sis; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: C505208:(6,7-dimethoxy-2,4-dihydroindeno(1,2-c)pyrazol-3-yl)(3-fluorophenyl)amine; D000970:Antineoplastic Agents; D007189:Indans; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011720:Pyrazoles; D000077214:Becaplermin; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor