Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase

David J. Augeri, Stephen J. O'Connor, Dave Janowick, Bruce Szczepankiewicz, Gerry Sullivan, John Larsen, Douglas Kalvin, Jerry Cohen, Edward Devine, Haichao Zhang, Sajeev Cherian, Badr Saeed, Shi Chung Ng, Saul Rosenberg

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Potent and selective non-thiol-containing inhibitors of protein farnesyltransferase are described. FTI-276 (1) was transformed into pyridyl ether analogue 19. The potency of pyridyl ether 19 was improved by modification of the biphenyl core to that of an o-tolyl substituted biphenyl core to give 29. In addition to 0.4 nM in vitro potency, 29 displayed 350 nM potency in whole cells as the parent carboxylic acid. The o-tolyl biphenyl core dramatically and unexpectedly enhanced the potency of other compounds as exemplified by 46, 47, 48, and 49.

Original languageEnglish (US)
Pages (from-to)4288-4300
Number of pages13
JournalJournal of medicinal chemistry
Issue number22
StatePublished - Oct 23 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Augeri, D. J., O'Connor, S. J., Janowick, D., Szczepankiewicz, B., Sullivan, G., Larsen, J., Kalvin, D., Cohen, J., Devine, E., Zhang, H., Cherian, S., Saeed, B., Ng, S. C., & Rosenberg, S. (1998). Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase. Journal of medicinal chemistry, 41(22), 4288-4300. https://doi.org/10.1021/jm980298s