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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.[1]

References

  1. Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy. O'Connor, S.J., Barr, K.J., Wang, L., Sorensen, B.K., Tasker, A.S., Sham, H., Ng, S.C., Cohen, J., Devine, E., Cherian, S., Saeed, B., Zhang, H., Lee, J.Y., Warner, R., Tahir, S., Kovar, P., Ewing, P., Alder, J., Mitten, M., Leal, J., Marsh, K., Bauch, J., Hoffman, D.J., Sebti, S.M., Rosenberg, S.H. J. Med. Chem. (1999) [Pubmed]
 
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