Abstract
7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals).
MeSH terms
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Alopecia / drug therapy*
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Animals
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Benzothiazoles / chemistry
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Benzothiazoles / pharmacology*
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Female
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Mice
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Mice, Inbred C57BL
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Receptors, Transforming Growth Factor beta / metabolism
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Smad2 Protein / antagonists & inhibitors
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Smad2 Protein / metabolism
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Smad3 Protein / antagonists & inhibitors
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Smad3 Protein / metabolism
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / metabolism
Substances
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Benzothiazoles
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Enzyme Inhibitors
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Imidazoles
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Receptors, Transforming Growth Factor beta
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Smad2 Protein
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Smad2 protein, mouse
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Smad3 Protein
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Smad3 protein, mouse
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Transforming Growth Factor beta
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imidazole
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Tgfbr1 protein, mouse
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benzothiazole