Identification of novel inhibitors of the transforming growth factor β1 (TGF-β1) type 1 receptor (ALK5)

被引：279

作者：

Callahan, JF

Burgess, JL

Fornwald, JA

Gaster, LM

Harling, JD

Harrington, FP

Heer, J

Kwon, C

Lehr, R

Mathur, A

Olson, BA

Weinstock, J

Laping, NJ

机构：

[1] GlaxoSmithKline Pharmaceut, Dept Med Chem, Collegeville, PA 19426 USA

[2] GlaxoSmithKline Pharmaceut, Dept Med Chem, King Of Prussia, PA 19406 USA

[3] GlaxoSmithKline Pharmaceut, Dept Renal Pharmacol, King Of Prussia, PA 19406 USA

[4] GlaxoSmithKline Pharmaceut, Dept Prot Biochem, King Of Prussia, PA 19406 USA

[5] GlaxoSmithKline Pharmaceut, Dept Gene Express Sci, King Of Prussia, PA 19406 USA

[6] Dept Med Chem, Harlow CM19 5AD, Essex, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 05期

关键词：

D O I：

10.1021/jm010493y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.

引用

页码：999 / 1001

页数：3

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