5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazo le derivatives as potent and selective transforming growth factor-[beta] type I receptor inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 24; pp. 7128 - 7138
• Main Authors: Amada, Hideaki, Sekiguchi, Yoshinori, Ono, Naoya, Koami, Takeshi, Takayama, Tetsuo, Yabuuchi, Tetsuya, Katakai, Hironori, Ikeda, Akiko, Aoki, Mari, Naruse, Takumi, Wada, Reiko, Nozoe, Akiko, Sato, Masakazu
• Format: Journal Article
• Language: English
• Published: 15-12-2012
• Subjects: Enzymes; Lotions; Phosphorylation; Skin; Smad2 protein; Topical application
• ISSN: 0968-0896
• DOI: 10.1016/j.bmc.2012.09.066

A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazo l e derivatives was synthesized as transforming growth factor-[beta] (TGF-[beta]) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-[beta]-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC50 = 5.5 nM) as well as inhibitory activity against TGF-[beta]-induced Smad2/3 phosphorylation at a cellular level (IC50 = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).