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

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 AL...

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Published inJournal of medicinal chemistry Vol. 45; no. 5; pp. 999 - 1001
Main Authors 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
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 28.02.2002
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
CELLS
TGF-BETA
KINASE
EXTRACELLULAR-MATRIX
FACTOR-BETA-1
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Summary: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.
ISSN:0022-2623
DOI:10.1021/jm010493y