Antitumor activity of 5-aryl-2,3-dihydroimidazo[2,1-a]isoquinolines.
A series of 5-aryl-2,3-dihydroimidazo[2,1-a]isoquinolines previously reported to be platelet activating factor (PAF) receptor antagonists were evaluated for potential antitumor activity. Several compounds, such as the 5-(4'-tert-butylphenyl) (65), 5-[4'-(trimethylsilyl)phenyl] (69), and 5-(4'-cyclohexylphenyl) (71) analogs showed very good cytotoxicity against several tumor cell lines. 5-[4'-(Piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1- a]isoquinoline (SDZ 62-434, 53) was more effective on a milligram per kilogram basis than the clinical cytostatic agent edelfosine (1) in increasing survivors and decreasing tumor volume in the oral mouse Meth A fibrosarcoma assay. It was selected for further development and is currently in phase I clinical trials in cancer patients.
Houlihan
W J
WJ
Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey 07936.
Munder
P G
PG
Handley
D A
DA
Cheon
S H
SH
Parrino
V A
VA
D000818:Animals; D000970:Antineoplastic Agents; D001667:Binding, Competitive; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010972:Platelet Activating Factor / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007546:Isoquinolines; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor