Discovery of a series of cyclohexylethylamine-containing protein farnesyltransferase inhibitors exhibiting potent cellular activity

Synthesis of a library of secondary benzylic amines based on the Sebti-Hami lton type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6 as a potent enzyme inhibitor (IC50 Of 8 nM) which lacked the problematic thiol residue which had been a common theme in many of the more important FTase inhibitors reported to date. It has previ ously been disclosed that addition of o-tolyl substitution to FTase inhibit ors of the general description 2 had a salutary effect on both FTase inhibi tion and inhibition of Ras prenylation in whole cells. Combination of these two observations led us to synthesize 7, a potent FTase inhibitor which di splayed an IC50 of 0.16 nM for in vitro inhibition of FTase and an EC50 of 190 nM for inhibition of whole cell Ras prenylation. Modification of 7 by c lassical medicinal chemistry led to the discovery of a series of potent FTa se inhibitors, culminating in the identification of 25 which exhibited an I C50 Of 0.20 nM and an EC50 of 4.4 nM. In vivo tests in a nude mouse xenogra ft model of human pancreatic cancer (MiaPaCa cells) showed that oral dosing of 25 gave rise to impressive attenuation of the growth of this aggressive tumor cell line.