Second-generation peptidomimetic inhibitors of protein farnesyltransferasedemonstrating improved cellular potency and significant in vivo efficacy

The synthesis and evaluation of analogues of previously reported farnesyltr ansferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring result ed in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitu tion of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modi fication afforded 30, which demonstrated a dramatically improved pharmacoki netic profile. Compounds 26 and 29 demonstrated significant in vivo efficac y in nude mice inoculated with MiaPaCa-2, a human pancreatic tumorderived c ell line.