201. Synthesis and activity of 1-aryl-1'-imidazolyl methyl ethers as non-thiol farnesyltransferase inhibitors.
- Author
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Li Q, Wang GT, Li T, Gwaltney SL 2nd, Woods KW, Claiborne A, Wang X, Gu W, Cohen J, Stoll VS, Hutchins C, Frost D, Rosenberg SH, and Sham HL
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Transformed, Crystallography, X-Ray, Ethers chemistry, Ethers pharmacology, Farnesyltranstransferase, Genes, ras, Humans, Imidazoles chemistry, Imidazoles pharmacology, Mice, Models, Molecular, NIH 3T3 Cells, Quinolones chemistry, Structure-Activity Relationship, Alkyl and Aryl Transferases antagonists & inhibitors, Alkyl and Aryl Transferases chemistry, Antineoplastic Agents chemical synthesis, Ethers chemical synthesis, Imidazoles chemical synthesis
- Abstract
A series of imidazole-containing methyl ethers (4-5) have been designed and synthesized as potent and selective farnesyltransferase inhibitors (FTIs) by transposition of the D-ring to the methyl group on the imidazole of the previously reported FTIs 3. Several compounds such as 4h and 5b demonstrate superior enzymatic activity to the current benchmark compound tipifarnib (1) with IC(50) values in the lower subnanomolar range, while maintaining excellent cellular activity comparable to tipifarnib. The compounds are characterized as being simple, easier to make, and possess no chiral center involved.
- Published
- 2004
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