ABSTRACT
A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.
Subject(s)
Alanine/analogs & derivatives , Angiogenesis Inhibitors/chemical synthesis , Pyrroles/chemical synthesis , Triazines/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Alanine/chemical synthesis , Alanine/pharmacokinetics , Alanine/pharmacology , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous , Triazines/pharmacokinetics , Triazines/pharmacologyABSTRACT
Tetrahydroquinoline-based small molecule inhibitors of farnesyltransferase (FT) have been identified. Lead compounds were shown to have nanomolar to sub-nanomolar activity in biochemical assays with excellent potency in a Ras-mutated cellular reversion assay. BMS-316810 (9e), a 0.7 nM FT inhibitor, was orally-active in a nude mouse tumor allograft efficacy study.
