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

Abstract

A series of new pyridazin-3(2H)-one derivatives (3 and 4) were evaluated for their in vitro affinity toward both alpha(1)- and alpha(2)-adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the alpha(1)-adrenoceptor, with K(i) 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 alpha(1)-AR affinity (1.9 nM), was also shown to be a highly selective alpha(1)-AR antagonist, the affinity ratio for alpha(2)- and alpha(1)-adrenoceptors being 274. To gain insight into the structural features required for alpha(1) 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.

Improved synthesis of 2-arylhydrazono-3-hydroxy-1-propanones and their utility in efficient synthesis of pyridazine derivatives

“…This key structure is a constituent in many biologically active substances. [5][6][7][8][9][10][11][12] Recently we reviewed synthetic approaches to pyridazines and condensed pyridazines. 13 We have previously reported the synthesis of arylhydrazonals 1a-c by heating of -methyl-ketone with dimethylformamide dimethyl acetal (DMFDMA) for five hours in xylene and coupling the resulting enaminones with an aromatic diazonium chloride (Scheme 1).…”

Convenient synthesis of some methyl-N-[2-(3-oxo-6-p-tolyl-2,3,4,5-tetrahydropyridazin-2-yl)-acetylamino]amino acid esters

“…Recently, a number of 6-aryl-4,5-dihydropyridazin-3(2H)-ones have been reported to possess antimicrobial, 1,2 potent analgesic, 3 anti-inflammatory, [3][4][5][6][7] antifeedant, 8 herbicidal, 9 antihypertensive, [10][11][12] antiplatelet activities, [13][14][15] anticancer effects 16 and other anticipated biological 17 and pharmacological properties. 8,19 Imazodan I is reported to show ionotropic properties comparable to milrinone and amrinone II.…”

Design, Synthesis and Biological Evaluation of Novel 7-Mercaptocoumarin Derivatives as α₁-Adrenoceptor Antagonists

“…[1][2][3][4][5] Accordingly, α 1 -AR antagonists are promising therapeutic agents for treatment of BPH. [6][7][8][9][10][11][12][13][14] The α 1 -ARs belong to the superfamily of G-protein-coupled seven transmembrane helix receptors (GPCR) and comprise of three distinct subtypes that have been clearly identified by both pharmacological and binding studies. To date, their subtypes have been classified into, α 1A , α 1B , α 1D and their corresponding cloned counterparts termed α 1a , α 1b , α 1d , respectively.…”

“…Recently, research efforts in the field of α 1 -AR antagonists have led to the identification of several pharmacophore models and most of them consisted of five common features: one positive ionizable group (PI), one hydrogen bond acceptor (HBA) and three hydrophobic features (HY1-3). 6,7) Many phenylpiperazine derivatives containing different heterocyclic rings show high affinity for α 1 -ARs and their chemical groups can also nicely map to the features of the model. [7][8][9][10][11][12][13][14] Usually, the HY1 and HY2 can be filled by substituted phenyl ring of the phenylpiperazine moiety, while the latter satisfy the PI with its positive ionisable nitrogen atom.…”

“…6,7) Many phenylpiperazine derivatives containing different heterocyclic rings show high affinity for α 1 -ARs and their chemical groups can also nicely map to the features of the model. [7][8][9][10][11][12][13][14] Usually, the HY1 and HY2 can be filled by substituted phenyl ring of the phenylpiperazine moiety, while the latter satisfy the PI with its positive ionisable nitrogen atom. The remaining features, HBA and HY3, can be matched by hydrogen bond acceptor moiety and hydrophobic group of a heterocyclic ring system, respectively 6,13,14,18) (Fig.…”