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Synthesis and receptor binding activity of novel 5-((Tetrazole-5yl)- phenyl) thiophenes

Introduction Angiotensin II receptor antagonists (sartans) are a new class of pharmacological agents for treatment of hypertension. They act as selective blockers (antagonists) of the most potent vasoconstrictor, angiotensin II (AII) AT1 receptors. Aiming to explain the influence of the structural changes on the biological activity, the synthesis and the receptor binging activity of structural analogues of sartan, derivatives of 5-[2-(tetrazole-5- yl)phenyl]thiophene is described. Materials and methods The novel sustituted heterobiaryls were efficiently prepared by multistep synthesis starting from methyl 2-aminobenzoate. Receptor binding activity of the newly synthesized compounds was tested on glomeruli isolated from rat kidney cortex using radioactively labelled angiotensin II ([3H]AII). Obtained results were compared with the commercially antihypertensive drug valsartan. Results Modification of Gomberg-Bachmann-Hey reaction was proved to be a convenient method for the preparation of multigram scale synthesis of target intermediate 2-(5-Formyl-thiophen-2- yl)benzonitrile. Further synthesis included reductive amination, acylation, tetrazole formation and finally the removal of protecting ester function. In all binding experiments angiotensin II displaced [3H]AII binding to isolated rat glomeruli in concentration 10 µM. Non-specific binding did not occur in more than 40% of [3H]AII total binding. In concentrations ranging from 1 nM to 10 μM, AII and valsartan inhibited completely the binding of [3H]AII on AT1 receptors from isolated rat glomeruli. Novel 5-[2-(tetrazole-5-yl)phenyl]thiophene derivatives were found to be two orders of magnitude less active than valsartan. Conclusions Replacement of the central phenyl ring of the biphenyl moiety of valsartan with a heteroaromatic thiophene decreases the binding affinity and inhibitory effect of the compounds.

angiotensin II (AII) AT1 receptors; 5-[2-(tetrazole-5-yl)phenyl]thiophenes; receptor binding

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