engleski

Design, Synthesis and in vitro Activity of AT1 Angiotensin II receptor Antagonists Based on the Novel 5-[2-(tetrazole-5- yl)phenyl]thiophenes

Angiotensin II receptor antagonists, also known as sartans are a new class of pharmacological agents for treatment of hypertension. Despite the structural differences, all commercial sartans characterise the same mechanism on molecular level. They act as selective blockers (antagonists) of the most potent vasoconstrictor, angiotensin II AT1 receptors. A new series of nonpeptide angiotensin II receptor antagonists, structural analogs of sartan, derivatives of 5-[2-(tetrazole-5- yl)phenyl]thiophene is described. Biological activity of the newly synthesised compounds was tested on two in vitro models on glomeruli isolated from rat kidney cortex. Obtained results were compared with the commercially antihypertensive drug known under the generic name valsartan (N-Valeroyl-N-{; ; [2'-(1H- tetrazole-5-yl)[1, 1'-biphenyl]-4-yl]methyl}; ; - L- valine). Replacement of the central phenyl ring of the biphenyl moiety of valsartan with a heteroaromatic thiophene increases the ability of compounds to antagonise the vasoconstriction induced by AII on isolated glomeruli. Heterobiaryl lauroyl derivative (N-lauroyl-N- {; ; 5-[2-(tetrazole-5-yl)phenyl]thiophen-2- yl}; ; methyl-L-valine) act as the most potent blocker and competitive inhibitor on angiotensin II evoked contractile response (KB = 26.3 nmol/dm3) by more than one order of magnitude higher estimated affinity for AT1 receptors than available valsartan (KB = 562.3 nmol/dm3). Heterobiaryl compounds with lengthened aliphatic chain on lipophilic acyl moiety show higher antagonism effect. The new compounds were examined for binding affinity to AT1 receptor on glomeruli using radioactive labelled angiotensin II ([3H]AII) as radioligand. 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. Heterobiaryl valeroyl derivative (N- valeroyl-N-{; ; 5-[2-(tetrazole-5- yl)phenyl]thiophen-2-yl}; ; methyl-L-valine, Ki = 525.2 nmol/dm3) and lauroyl derivative (Ki = 563.1 nmol/dm3) show the highest binding affinity, but still two orders of magnitude lower than valsartan (Ki = 4.2 nmol/dm3). It was found that the length of aliphatic chain on lipophilic acyl moiety also affected to inhibitory effect. Structural analogs of valeroyl derivative and phenylacetyl derivative (N-phenylacetyl-N-{; ; 5-[2-(tetrazole-5- yl)phenyl]thiophen-2-yl}; ; methyl-L-valine) with elongated alkyl chain exhibit lower binding affinity.

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

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