Design, synthesis, and structure–activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitors

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,...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2005-04, Vol.15 (7), p.1895-1899
Hauptverfasser:	Lombardo, Louis J., Camuso, Amy, Clark, John, Fager, Krista, Gullo-Brown, Johnni, Hunt, John T., Inigo, Ivan, Kan, David, Koplowitz, Barry, Lee, Francis, McGlinchey, Kelly, Qian, Ligang, Ricca, Carolyn, Rovnyak, George, Traeger, Sarah, Tokarski, John, Williams, David K., Wu, Laurence I., Zhao, Yufen, Manne, Veeraswamy, Bhide, Rajeev S.
Format:	Artikel
Sprache:	eng
Schlagworte:	Alkyl and Aryl Transferases - antagonists & inhibitors Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Biological and medical sciences BMS-316810 Cell Line, Tumor Drug Screening Assays, Antitumor Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Farnesyltransferase inhibitor Farnesyltranstransferase General aspects Medical sciences Mice Mice, Nude Pharmacology. Drug treatments Quinolines - chemical synthesis Quinolines - pharmacology Structure-Activity Relationship
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Zusammenfassung:	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. 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2005.02.004