Abstract
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.
MeSH terms
-
Alkyl and Aryl Transferases / antagonists & inhibitors*
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / pharmacology
-
Benzylamines / chemical synthesis
-
Benzylamines / pharmacology
-
Enzyme Inhibitors / chemical synthesis*
-
Enzyme Inhibitors / pharmacology
-
Ethers / chemical synthesis
-
Ethers / pharmacology
-
Humans
-
Mice
-
Mice, Nude
-
Neuropeptides / genetics
-
Neuropeptides / metabolism
-
Receptors, Tumor Necrosis Factor*
-
Signal Transduction / drug effects
-
Tumor Cells, Cultured
-
fas Receptor
Substances
-
Antineoplastic Agents
-
Benzylamines
-
Enzyme Inhibitors
-
Ethers
-
FAS protein, human
-
Fas protein, mouse
-
Neuropeptides
-
Receptors, Tumor Necrosis Factor
-
fas Receptor
-
Alkyl and Aryl Transferases
-
p21(ras) farnesyl-protein transferase