Design, synthesis and evaluation of small molecule imidazo[2,1-b] [1,3,4]thiadiazoles as inhibitors of transforming growth factor-β type-I receptor kinase (ALK5)

A new series of imidazo[2,1-b][1,3,4]thiadiazoles 5(a-g), 6(a-g), 9(a-i) and 12(a-h) were synthesized as transforming growth factor-beta (TGF-beta) 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-beta -induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. Compound 6d, 2-(5((2-cyclopropy1-6-(4-fluorophenyl) imidazo [2,1-b][1,3,4]thiadiazol-5-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl) acetic acid, shows prominent ALK5 inhibition (IC50 = 0.0012 mu M) and elective inhibition (91%) against the P38 alpha kinase at10 mu M. The binding mode of compound 6d by XP docking studies shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silica ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules. (C) 2014 Elsevier Masson SAS. All rights reserved.