Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier

被引：38

作者：

Rubenstein, SM ^{[1
]}

Baichwal, V ^{[1
]}

Beckmann, H ^{[1
]}

Clark, DL ^{[1
]}

Frankmoelle, W ^{[1
]}

Roche, D ^{[1
]}

Santha, E ^{[1
]}

Schwender, S ^{[1
]}

Thoolen, M ^{[1
]}

Ye, QP ^{[1
]}

Jaen, JC ^{[1
]}

机构：

[1] Tularik Inc, S San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2001年 / 44卷 / 22期

关键词：

D O I：

10.1021/jm000478d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [H-3]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2. Amides 3-5 showed no detectable signs of crossing the blood brain barrier, while amide 6 was found in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed in vivo from these amides, was found in significantly smaller amounts (approximately 20 to > 5000 times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6 approached that of T138067 and was better tolerated when administered to athymic. nude mice bearing MX-1 human mammary tumor xenografts.

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页码：3599 / 3605

页数：7

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