Computer--based drug design, synthesis and biological evaluation of new pyrimidinone derivatives linked to arylpiperazine and 2'-carbethoxy-biphenylylmethyl moeities as alpha1-adrenoceptor antagonists and angiotensin II AT1 receptor antagonists.

Two new series of pyrimidinone derivatives linked to arylpiperazine moieties and 2'-carbethoxy-biphenylmethyl moieties were designed, synthesized and biologically evaluated for their in vivo hypotensive activities. The design of arylpiperazine analogues (IIa-f, IIIa-c, VIIa.b, IX) was based upon structural modification of the newly discovered selective alpha1-AR antagonist drug; Urapidil. Compare/fit studies of these molecules with the previously generated and validated alpha1-AR antagonist hypothesis showed that these molecules have comparable affinities for the alpha1-AR antagonist hypothesis while compound IIIc had the highest fitting value. The in vivo biological evaluation of these compounds for their effects on blood pressure of normotensive cats in comparison to the lead compound prazosin, was consistent with the results of molecular modeling fit values. As expected, compound IIIc exhibited the highest hypotensive activity among the test set compounds. Meanwhile, the design of 2'-carbethoxy-biphenylylmethyl analogues (XIa,b) was based upon the molecular modeling simulation fitting of their carboxylic acid bioprecursors with the previously generated and validated Ang II receptor antagonist hypothesis. Such compare/fit studies predicted that the designed compounds (XIa,b) showed comparable fitting affinities between their de-esterified analogues and the Ang II antagonist pharmacophore. In vivo biological evaluation of these compounds for their effects on blood pressure of normotensive cats showed that compound Xla exhibited hypotensive activity more or less similar to losartan.