title: 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.
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).
authors: Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. hideaki.amada@po.rd.taisho.co.jp
authors: Hideaki
authors: H
authors: Amada
authors: Hajime
authors: H
authors: Asanuma
authors: Takeshi
authors: T
authors: Koami
authors: Atsushi
authors: A
authors: Okada
authors: Mayumi
authors: M
authors: Endo
authors: Yasuji
authors: Y
authors: Ueda
authors: Takumi
authors: T
authors: Naruse
authors: Akiko
authors: A
authors: Ikeda
mesh_terms: D000505:Alopecia / Q000188:drug therapy*; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051899:Smad2 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; C029899:imidazole; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse; C005465:benzothiazole