Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase

Authors
Augeri, DJ Janowick, D Kalvin, D Sullivan, G Larsen, J Dickman, D Ding, H Cohen, J Lee, J Warner, R Kovar, P Cherian, S Saeed, B Zhang, HC Tahir, S Ng, SC Sham, H Rosenberg, SH
Citation
Dj. Augeri et al., Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase, BIOORG MED, 9(8), 1999, pp. 1069-1074
Citations number
26
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
ISSN journal
0960894X → ACNP
Volume
9
Issue
8
Year of publication
1999
Pages
1069 - 1074
Database
ISI
SICI code
0960-894X(19990419)9:8<1069:PAOBNI>2.0.ZU;2-K
Abstract
Potent and orally bioavailable nonthiol-containing inhibitors of protein fa rnesyltransferase are described. Oral bioavailability was achieved by repla cement 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 ntaining the bioavailability inherent in 4. p-Chlorophenylfuran ether 24 is 0.7 nM in vitro (FTase) and is 32% bioavailable in the mouse, 30% bioavail able in rats, and 21% bioavailable in dogs. (C) 1999 Elsevier Science Ltd. All rights reserved.