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

Louis J Lombardo; Amy Camuso; John Clark; Krista Fager; Johnni Gullo-Brown; John T Hunt; Ivan Inigo; David Kan; Barry Koplowitz; Francis Lee; Kelly McGlinchey; Ligang Qian; Carolyn Ricca; George Rovnyak; Sarah Traeger; John Tokarski; David K Williams; Laurence I Wu; Yufen Zhao; Veeraswamy Manne; Rajeev S Bhide

doi:10.1016/j.bmcl.2005.02.004

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

Bioorg Med Chem Lett. 2005 Apr 1;15(7):1895-9. doi: 10.1016/j.bmcl.2005.02.004.

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, United States. [email protected]

PMID: 15780629
DOI: 10.1016/j.bmcl.2005.02.004

Abstract

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.

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Farnesyltranstransferase
Mice
Mice, Nude
Quinolines / chemical synthesis*
Quinolines / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
Quinolines
Alkyl and Aryl Transferases
Farnesyltranstransferase