Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase

Potent and orally bioavailable nonthiol-containing inhibitors of protein farnesyltransferase are described. Oral bioavailability was achieved by replacement of the pyridyl ether moiety of 1 with a 2-substituted furan ether to give 4. Potency was regained with 2,5-disubstituted furan ethers while maintaining the bioavailability inherent in 4. p-Chlorophenylfuran ether 24 is 0.7 nM in vitro (FTase) and is 32% bioavailable in the mouse, 30% bioavailable in rats, and 21% bioavailable in dogs. The syntheses and SAR of a series of non-cysteine-containing CAAX mimics are described. The 2,5-disubstituted furan ether 24 is potent and orally bioavailable.