Structure-based design of novel, urea-containing FKBP12 inhibitors

被引：61

作者：

Dragovich, PS

Barker, JE

French, J

Imbacuan, M

Kalish, VJ

Kissinger, CR

Knighton, DR

Lewis, CT

Moomaw, EW

Parge, HE

Pelletier, LAK

Prins, TJ

Showalter, RE

Tatlock, JH

Tucker, KD

Villafranca, JE

机构：

[1] Agouron Pharmaceuticals, Inc., San Diego, CA 92121

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1996年 / 39卷 / 09期

关键词：

D O I：

10.1021/jm950798a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The structure-based design and subsequent chemical synthesis of novel, urea-containing FKBP12 inhibitors are described. These compounds are shown to disrupt the cis-trans peptidylprolyl isomerase activity of FKBP12 with inhibition constants (K-i,K-app) approaching 0.10 mu M. Analyses of several X-ray crystal structures of FKBP12-urea complexes demonstrate that the urea-containing inhibitors associate with FKBP12 in a manner that is similar to, but significantly different from, that observed for the natural product FK506.

引用

页码：1872 / 1884

页数：13

共 75 条

[1] SUBSTRATE-SPECIFICITY FOR THE HUMAN ROTAMASE FKBP - A VIEW OF FK506 AND RAPAMYCIN AS LEUCINE (TWISTED AMIDE) PROLINE MIMICS [J].