Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase

…, J Larsen, D Dickman, H Ding, J Cohen, J Lee…

Index: Augeri, David J.; Janowick, Dave; Kalvin, Douglas; Sullivan, Gerry; Larsen, John; Dickman, Daniel; Ding, Hong; Cohen, Jerry; Lee, Jang; Warner, Robert; Kovar, Peter; Cherian, Sajeev; Saeed, Badr; Zhang, Haichao; Tahir, Steve; Ng, Shi-Chung; Sham, Hing; Rosenberg, Saul H. Bioorganic and Medicinal Chemistry Letters, 1999 , vol. 9, # 8 p. 1069 - 1074

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Citation Number: 26

Abstract

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, ...