title: 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.
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).
authors.affiliation: Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Saitama, Saitama 331-9530, Japan. hideaki.amada@po.rd.taisho.co.jp
authors.forename: Hideaki
authors.initials: H
authors.lastname: Amada
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sekiguchi
authors.forename: Naoya
authors.initials: N
authors.lastname: Ono
authors.forename: Takeshi
authors.initials: T
authors.lastname: Koami
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takayama
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yabuuchi
authors.forename: Hironori
authors.initials: H
authors.lastname: Katakai
authors.forename: Akiko
authors.initials: A
authors.lastname: Ikeda
authors.forename: Mari
authors.initials: M
authors.lastname: Aoki
authors.forename: Takumi
authors.initials: T
authors.lastname: Naruse
authors.forename: Reiko
authors.initials: R
authors.lastname: Wada
authors.forename: Akiko
authors.initials: A
authors.lastname: Nozoe
authors.forename: Masakazu
authors.initials: M
authors.lastname: Sato
mesh_terms: D000818:Animals; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D007093:Imidazoles; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse