Synthesis of novel Ral inhibitors: An in vitro and in vivo study.
Chemical synthesis was performed to produce a series of 6-amino-1,3-disubstituted-4-phenyl-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile compounds (14-57) which were characterized by1H NMR,13C NMR and LC/MS-MS. These compounds were assessed for their effect on the in vitro anchorage independent growth of human lung cancer cell line H2122 and IC50values calculated. Two of the more potent compounds, BQU057 40 and BQU082 57 also displayed a dose dependent effect on RalA and RalB activity in H2122 spheroids using the common RalBP1 pull-down assay. Mouse PK and tissue distribution studies on 40 and 57 were performed and demonstrated that parent drug was present in tumor 3.0h post ip (50mg/Kg) dose.
Department of Pharmacology, University of Colorado, Aurora, CO 80045, USA; Department of Surgery, University of Colorado, Aurora, CO 80045, USA.
Chao
C
Yan
Department of Pharmacology, University of Colorado, Aurora, CO 80045, USA; Department of Surgery, University of Colorado, Aurora, CO 80045, USA; University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA.
Dan
D
Theodorescu
Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA.
Bettina
B
Miller
Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA.
Amit
A
Kumar
Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA.
Vijay
V
Kumar
Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA.
David
D
Ross
Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA. Electronic address: michael.wempe@ucdenver.edu.
Michael F
MF
Wempe
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D020725:ral GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D009570:Nitriles; D011720:Pyrazoles; C483163:Ralb protein, human; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins
Chemical synthesis; Ral inhibitor; Tissue distribution