(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.
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).
Ho
Chih Y
CY
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Spring House Research and Early Development Site, Spring House, Pennsylvania 19477, USA.
Ludovici
Donald W
DW
Maharoof
Umar S M
US
Mei
Jay
J
Sechler
Jan L
JL
Tuman
Robert W
RW
Strobel
Eric D
ED
Andraka
Laura
L
Yen
Hwa-Kwo
HK
Leo
Gregory
G
Li
Jian
J
Almond
Harold
H
Lu
Hong
H
DeVine
Ann
A
Tominovich
Rose M
RM
Baker
Judith
J
Emanuel
Stuart
S
Gruninger
Robert H
RH
Middleton
Steven A
SA
Johnson
Dana L
DL
Galemmo
Robert A
RA
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*
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