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.
D019883:Alkyl and Aryl Transferases / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D003545:Cysteine / Q000737:chemistry*; D004285:Dogs; D051379:Mice; D008956:Models, Chemical; D051381:Rats