Discovery of 7-Methoxy-6-〔4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl〕-1,3-benzothiazole (TASP0382088) : A Potent and Selective Transforming Growth Factor-β Type Ⅰ Receptor Inhibitor as a Topical Drug for Alopecia

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  • Amada Hideaki
    Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd.
  • Asanuma Hajime
    Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd.
  • Koami Takeshi
    Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd.
  • Okada Atsushi
    Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd.
  • Endo Mayumi
    Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd.
  • Ueda Yasuji
    Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd.
  • Naruse Takumi
    Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd.
  • Ikeda Akiko
    Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd.

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  • Discovery of 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1<i>H</i>-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): A Potent and Selective Transforming Growth Factor-β Type I Receptor Inhibitor as a Topical Drug for Alopecia

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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).

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