Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase

被引:28
作者
Augeri, DJ [1 ]
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
机构
[1] Abbott Labs, Dept Canc Res, Abbott Pk, IL 60064 USA
[2] Abbott Labs, Dept Combinatorial Chem, Div Pharmaceut Prod, Abbott Pk, IL 60064 USA
关键词
D O I
10.1016/S0960-894X(99)00144-4
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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. (C) 1999 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:1069 / 1074
页数:6
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