Thyroid receptor ligands.: Part 2:: Thyromimetics with improved selectivity for the thyroid hormone receptor beta

被引：44

作者：

Hangeland, JJ ^{[1
]}

Doweyko, AM

Dejneka, T

Friends, TJ

Devasthale, P

Mellström, K

Sandberg, J

Grynfarb, M

Sack, JS

Einspahr, H

Färnegårdh, M

Husman, B

Ljunggren, J

Koehler, K

Sheppard, C

Malm, J

Ryono, DE

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA

[2] Karo Bio AB, Novum, S-14157 Huddinge, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 13期

关键词：

thyromimetics; thyroid hormone receptor;

D O I：

10.1016/j.bmcl.2004.04.032

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A set of thyromimetics having improved selectivity for TR-beta1 were prepared by replacing the 3'-isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3'-phenyl moiety bearing small hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed with TR-beta1 LBD shows methionine 442 to be displaced by the bulky R3' phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand-receptor complex retains full agonist activity. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：3549 / 3553

页数：5

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