Design, synthesis, and evaluation of novel 4-thiazolylimidazoles as inhibitors of transforming growth factor-β type I receptor kinase

Hideaki Amada; Yoshinori Sekiguchi; Naoya Ono; Yuko Matsunaga; Takeshi Koami; Hajime Asanuma; Fumiyasu Shiozawa; Mayumi Endo; Akiko Ikeda; Mari Aoki; Natsuko Fujimoto; Reiko Wada; Masakazu Sato

doi:10.1016/j.bmcl.2012.01.066

Design, synthesis, and evaluation of novel 4-thiazolylimidazoles as inhibitors of transforming growth factor-β type I receptor kinase

Bioorg Med Chem Lett. 2012 Mar 1;22(5):2024-9. doi: 10.1016/j.bmcl.2012.01.066. Epub 2012 Jan 28.

Authors

Hideaki Amada¹, Yoshinori Sekiguchi, Naoya Ono, Yuko Matsunaga, Takeshi Koami, Hajime Asanuma, Fumiyasu Shiozawa, Mayumi Endo, Akiko Ikeda, Mari Aoki, Natsuko Fujimoto, Reiko Wada, Masakazu Sato

Affiliation

¹ Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama, Saitama 331-9530, Japan. hideaki.amada@po.rd.taisho.co.jp

PMID: 22325945
DOI: 10.1016/j.bmcl.2012.01.066

Abstract

A novel series of 4-thiazolylimidazoles was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. N-{[5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-2-yl]methyl}butanamide 20, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC(50)=8.2nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC(50)=32nM).

MeSH terms

Drug Design
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / pharmacology*
Models, Molecular
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
Receptors, Transforming Growth Factor beta / metabolism
Smad2 Protein / metabolism
Smad3 Protein / metabolism
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology

Substances

Imidazoles
Protein Kinase Inhibitors
Receptors, Transforming Growth Factor beta
Smad2 Protein
Smad3 Protein
Thiazoles
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type I
TGFBR1 protein, human