Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase. |
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| Authors: | D J Augeri D Janowick D Kalvin G Sullivan J Larsen D Dickman H Ding J Cohen J Lee R Warner P Kovar S Cherian B Saeed H Zhang S Tahir S C Ng H Sham S H Rosenberg |
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| Institution: | Department of Cancer Research, Abbott Laboratories, Abbott Park, IL 60064, USA. |
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| 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, and 21% bioavailable in dogs. |
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