Synthesis, Biological Evaluation, and Pharmacophore Generation of New Pyridazinone Derivatives with Affinity toward α1- and α2-Adrenoceptors

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Abstract
A series of new pyridazin-3(2H)-one derivatives (3 and 4) were evaluated for their in vitro affinity toward both α1- and α2-adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the α1-adrenoceptor, with Ki values in the low nanomolar range. The polymethylene chain constituting the spacer between the furoylpiperazinyl pyridazinone and the arylpiperazine moiety was shown to influence the affinity and selectivity of these compounds. Particularly, a gradual increase in affinity was observed by lengthening the polymethylene chain up to a maximum of seven carbon atoms. In addition, compound 3k, characterized by a very interesting α1-AR affinity (1.9 nM), was also shown to be a highly selective α1-AR antagonist, the affinity ratio for α2- and α1-adrenoceptors being 274. To gain insight into the structural features required for α1 antagonist activity, the pyridazinone derivatives were submitted to a pharmacophore generation procedure using the program Catalyst. The resulting pharmacophore model showed high correlation and predictive power. It also rationalized the relationships between structural properties and biological data of, and external to, the pyridazinone class.

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