Imidazole-containing diarylether and diarylsulfone inhibitors of farnesyl-protein transferase

The design and syntheses of non-thiol inhibitors of farnesyl-protein transferase are described. Optimization of cysteine-substituted diarylethers led to highly potent imidazole-containing diarylethers and diarylsulfones. Polar diaryl linkers dramatically improved potency and gave highly cell active...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 1999-12, Vol.9 (23), p.3301-3306
Hauptverfasser:	Dinsmore, Christopher J., Williams, Theresa M., O'Neill, Timothy J., Liu, Dongming, Rands, Elaine, Culberson, J.Christopher, Lobell, Robert B., Koblan, Kenneth S., Kohl, Nancy E., Gibbs, Jackson B., Oliff, Allen I., Graham, Samuel L., Hartman, George D.
Format:	Artikel
Sprache:	eng
Schlagworte:	Alkyl and Aryl Transferases - antagonists & inhibitors Antineoplastic agents Biological and medical sciences Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Ethers - chemistry General aspects Humans Imidazoles - chemistry Imidazoles - pharmacology Magnetic Resonance Spectroscopy Medical sciences Molecular Structure Pharmacology. Drug treatments Sulfones - chemistry
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Zusammenfassung:	The design and syntheses of non-thiol inhibitors of farnesyl-protein transferase are described. Optimization of cysteine-substituted diarylethers led to highly potent imidazole-containing diarylethers and diarylsulfones. Polar diaryl linkers dramatically improved potency and gave highly cell active compounds. The synthesis and SAR of a series of imidazole-substituted diarylethers and diarylsulfones as farnesyl-protein transferase inhibitors are described.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(99)00605-8