Synthesis, biological evaluation, and pharmacophore generation of new pyridazinone derivatives with affinity toward alpha(1)- and alpha(2)-adrenoceptors.

摘要: A series of new pyridazin-3(2H)-one derivatives (3 and 4) were evaluated for their in vitro affinity toward both alpha(1)- alpha(2)-adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities the alpha(1)-adrenoceptor, with K(i) values low nanomolar range. The polymethylene chain constituting spacer between furoylpiperazinyl pyridazinone arylpiperazine moiety was shown to influence selectivity these compounds. Particularly, a gradual increase observed lengthening up maximum seven carbon atoms. In addition, compound 3k, characterized very interesting alpha(1)-AR (1.9 nM), also be highly selective antagonist, ratio alpha(2)- alpha(1)-adrenoceptors being 274. To gain insight into structural features required alpha(1) antagonist activity, submitted pharmacophore generation procedure using program Catalyst. resulting model high correlation predictive power. It rationalized relationships properties biological data of, external to, class.