Design, Synthesis and Evaluation of Small Molecules as ALK5 Inhibitors

A new series of imidazo[2,1-b][1,3,4]thiadiazoles 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. One of the compound from this series displayed prominent ALK5 inhibition (IC50 = 0.0012 µM) and elective inhibition (91%) against the P38 kinase at 10 µM. The binding mode of this compound by XP docking studies showed that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use, thereby indicating their potential as a drug-like molecules.

Autorentext

Dr. R. Karpoormath is professor at the faculty in the Dis. of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban, South Africa. His research interests are: target based drug design (HIV, Cancer and TB), Methodology development and development of electroanalytical method to trace biological, organic species with modified electrodes.