Computer-aided simulation was used to design and synthesize nine novel fluorinated thrombin inhibitor derivatives. These compounds were confirmed by spectral analyses ((1)H NMR, (13)C NMR, and FT-ICR-MS). Their inhibitory activities against thrombin enzyme were evaluated by chromogenic assay. All the derivatives demonstrated thrombin inhibitory activity in vitro. Five of these compounds exerted more potent effects against thrombin enzyme compared with the reference drug argatroban. Compound 3-(2-(((4-carbamimidoylphenyl)amino)methyl)-1-ethyl-N-(2-fluoro-phenyl)-1H-benzo[d]imidazole-5-carboxamido)propanoic acid (IC50 = 3.52 ± 0.32 nmol/L) was a more potent inhibitor of thrombosis than argatroban (IC50 = 9.46 ± 0.92 nmol/L).
Keywords: Argatroban; Chromogenic assay; Docking; Fluorine; Thrombin inhibitor.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.