Synthesis and biological affinity of new imidazo- and indol-arylpiperazine derivatives: Further validation of a pharmacophore model for α1-adrenoceptor antagonists (original) (raw)
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Journal of Medicinal Chemistry, 2002
As a part of a program aimed at discovering compounds endowed with R 1 -adrenoceptor (AR) blocking properties, in this paper we describe the synthesis and biological characterization of the compounds designed to fully match a three-dimensional pharmacophore model for R 1 -AR antagonists previously developed by our research group. Accordingly, the structure of trazodone (1), identified during a database search performed by using the model as a 3D query, was chosen as the starting point for this study and modified following suggestions derived from a literature survey. In particular, the triazolopyridine moiety of trazodone was replaced with different heteroaromatic rings (such as imidazole, benzimidazole, and indole), and a pyridazin-3(2H)-one moiety was inserted into the scaffold of the new compounds to increase the overall length of the molecules and to allow for a complete fit into all the pharmacophore features. Our aim was also to study the influence of the position of both the chloro and the methoxy groups on the piperazine phenyl ring, as well as the effect of the lengthening or shortening of the polymethylene spacer linking the phenylpiperazine moiety to the terminal heterocyclic portion. Compounds obtained by such structural optimization share a 6-(imidazol-1-yl)-, 6-(benzimidazol-1-yl)-, or 6-(indol-1-yl)pyridazin-3(2H)-one as a common structural feature that represents an element of novelty in the SAR of arylpiperazine compounds acting toward R 1 -AR. Biological evaluation by radioligand receptor binding assays toward R 1 -AR, R 2 -AR, and 5-HT 1A serotoninergic receptors indicated compounds characterized by very good R 1 -AR affinity and selectivity. Very interestingly, chemical features (such as the o-methoxyphenylpiperazinyl moiety and an alkyl spacer of three or four methylene units) that generally do not allow for 5-HT 1A /R 1 selectivity led to compounds 2c and 6c with a 5-HT 1A /R 1 ratio of 286 and 281, respectively. Finally, compounds with the best R 1 -AR affinity profile (2c, 5f, and 6c) were demonstrated to be R 1 -AR antagonists.
Bioorganic & Medicinal Chemistry, 2008
In the search for new antiarrhythmic agents, some active 2-methoxyphenylpiperazine derivatives of phenytoin were obtained as a chemical modification of compound AZ-99 (3-ethyl-1-[2-hydroxy-3-(4-phenylpiperazin-1-yl)-propyl]-2,4-dioxo-5,5diphenylimidazolidine). These compounds possessed structural properties similar to those of a 1 -adrenoceptor antagonists. In the present study, the affinities of the 2-methoxyphenylpiperazine derivatives (1a-3a) for a 1 -and a 2 -adrenoceptors were evaluated using radioligand ([ 3 H]prazosin, [ 3 H]clonidine) binding assays. In the next step, a new series of phenylpiperazine derivatives of phenytoin (4a-16a) containing 2-methoxyphenyl-, 2-ethoxyphenyl-, 2-pyridyl-or 2-furoylpiperazine moiety, as well as, various ester or alkyl substituents at 3-position of hydantoin ring were synthesized. The newly synthesized compounds were tested for their affinity to a 1and a 2 -adrenoceptors. They have shown affinities for a 1 -adrenoceptors at nanomolar to submicromolar range. Some compounds were moderately selective ligands of a 1 -adrenoceptors. Selected compounds (3a-5a, 7a, 13a, 14a) were also evaluated for their a 1 -adrenoceptor antagonistic properties in functional bioassays. A SAR study indicated that the most active compounds contain 2-alkoxyphenylpiperazine moieties and methyl or 2-methylpropionate substituent at 3-N position in hydantoin. The exchange of 2-alkoxyphenyl moiety into 2-furoyl or 2-pyridyl group significantly decreased affinities for a 1 -adrenoceptors. Molecular modelling results obtained using conformational analysis CONFLEX and PM5 method for geometry optimization, allowed for comparison of the spatial properties of tested compounds with pharmacophore model created by Barbaro et al. for the ideal a 1 -adrenoceptor antagonist.
Journal of medicinal chemistry, 1996
A series of new bicyclohydantoin-arylpiperazines was prepared and evaluated for affinity at 5-HT1A, alpha 1, and D2 receptors. Most of the compounds showed very low affinity for D2 receptors, and most of them demonstrated moderate to high affinity for 5-HT1A and alpha 1 receptor binding sites. SAR observations indicated that the length of the alkyl chain between the arylpiperazine and the hydantoin moiety is of great importance for 5-HT1A/alpha 1 affinity and selectivity, n = 1 being the optimal value. Compound 1h, 2-[[4-(o-methoxyphenyl)piperazin-1-yl] methyl]-1,3-dioxoperhydroimidazo [1,5-alpha]pyridine, bound at 5-HT1A sites with nanomolar affinity (Ki = 31.7 nM) and high selectivity over alpha 1, D2, and 5-HT2A receptors (Ki > 1000, > 10 000, and > 1000 nM, respectively). Preliminary studies showed that this agent is probably functioning as a partial to full 5-HT1A agonist, and it displayed anxiolytic activity on the social interaction test in mice.
Bioorganic & Medicinal Chemistry, 2011
The study is focused on (2-alkoxy)phenylpiperazine derivatives of 1-(2-hydroxy-3-(4-arylpiperazin-1yl)propyl)-5,5-diphenylimidazolidine-2,4-dione with alkyl or ester substituents at N3 of hydantoin ring, as well as a new designed and synthesized series of compounds with a free N3H group or N3-acetic acid terminal fragment. The compounds were assessed on their affinity for 5-HT 1A and a 1 -adrenoceptors and evaluated in functional bioassays for antagonistic properties. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) and DFT methods (B3LYP functional, Gaussian 0.3) were used to investigate 3D structure of the compounds. SAR analysis was based on two pharmacophore models, the one described by Barbaro et al. for a 1 -adenoceptor antagonist and the model of Lepailleur et al. for 5-HT 1A receptor ligands. All compounds exhibited significant to moderate affinities for 5-HT 1A receptors in nanomolar range (7-610 nM). The highest activity (7 nM) and selectivity (17.38) for 5-HT 1A was observed for 1-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)-3-methyl-5,5-diphenylimidazolidine-2,4dione (13a). Among new synthesized compounds 1-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1yl)propyl)-5,5-diphenylimidazolidine-2,4-dione hydrochloride (20a) displayed the highest affinity (16.6 nM) and selectivity (5.72) for a 1 -AR.
Journal of Medicinal Chemistry, 2001
A series of new pyridazin-3(2H)-one derivatives (3 and 4) were evaluated for their in vitro affinity toward both R 1 -and R 2 -adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the R 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 R 1 -AR affinity (1.9 nM), was also shown to be a highly selective R 1 -AR antagonist, the affinity ratio for R 2 -and R 1 -adrenoceptors being 274. To gain insight into the structural features required for R 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.