2. Academic Validation
  3. 5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors

5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors

  • Bioorg Med Chem. 2012 Dec 15;20(24):7128-38. doi: 10.1016/j.bmc.2012.09.066.
Hideaki Amada 1,  Yoshinori Sekiguchi,  Naoya Ono,  Takeshi Koami,  Tetsuo Takayama,  Tetsuya Yabuuchi,  Hironori Katakai,  Akiko Ikeda,  Mari Aoki,  Takumi Naruse,  Reiko Wada,  Akiko Nozoe,  Masakazu Sato
Affiliations

Affiliation

  • 1 Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Saitama, Saitama 331-9530, Japan. hideaki.amada@po.rd.taisho.co.jp
PMID: 23117174 DOI: 10.1016/j.bmc.2012.09.066
Abstract

A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-β (TGF-β) 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-β-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 (IC(50) = 5.5 nM) as well as inhibitory activity against TGF-β-induced SMAD2/3 phosphorylation at a cellular level (IC(50) = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited SMAD2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated Animals).

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