Potent inhibitors of protein farnesyltransferase: heteroarenes as cysteine replacements

W Shen; S Fakhoury; G Donner; K Henry; J Lee; H Zhang; J Cohen; R Warner; B Saeed; S Cherian; S Tahir; P Kovar; J Bauch; S C Ng; K Marsh; H Sham; S Rosenberg

doi:10.1016/s0960-894x(99)00080-3

Potent inhibitors of protein farnesyltransferase: heteroarenes as cysteine replacements

Bioorg Med Chem Lett. 1999 Mar 8;9(5):703-8. doi: 10.1016/s0960-894x(99)00080-3.

Authors

W Shen¹, S Fakhoury, G Donner, K Henry, J Lee, H Zhang, J Cohen, R Warner, B Saeed, S Cherian, S Tahir, P Kovar, J Bauch, S C Ng, K Marsh, H Sham, S Rosenberg

Affiliation

¹ Cancer Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, USA.

PMID: 10201832
DOI: 10.1016/s0960-894x(99)00080-3

Abstract

Synthesis and biological evaluation of heteroarenes as reduced cysteine replacements are described. Of the heteroaryl groups examined with respect to FT inhibitor FTI-276 (1), pyridyl was the replacement found to be most effective. Substitutions at C4 of the pyridyl moiety did not affect the in vitro activity. Compound 9a was found to have moderate in vivo bioavailability.

MeSH terms

3T3 Cells
Alkyl and Aryl Transferases / antagonists & inhibitors*
Animals
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology
Epoxy Compounds / chemical synthesis*
Epoxy Compounds / pharmacokinetics
Epoxy Compounds / pharmacology
Genes, ras / drug effects
Mice
Rats
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Epoxy Compounds
Alkyl and Aryl Transferases
p21(ras) farnesyl-protein transferase