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 mai...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 9; no. 8; pp. 1069 - 1074
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 19-04-1999 Elsevier
Subjects:	Alkyl and Aryl Transferases - administration & dosage Alkyl and Aryl Transferases - antagonists & inhibitors Alkyl and Aryl Transferases - chemical synthesis Alkyl and Aryl Transferases - pharmacokinetics Animals Antineoplastic agents Biological and medical sciences Biological Availability Cysteine - chemistry Dogs General aspects Medical sciences Mice Models, Chemical Pharmacology. Drug treatments Rats Antineoplastic agent Rat Furan derivatives Farnesyl-diphosphate farnesyltransferase Structure activity relation Chlorine Organic compounds Chemical synthesis Dog Fissipedia Carnivora Enzyme Transferases Rodentia Benzene derivatives Oral administration Enzyme inhibitor Bioavailability In vitro Sulfur containing aminoacid In vivo Vertebrata Mammalia Mouse Biphenyl derivatives Animal Pharmacokinetics
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(99)00144-4