Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluation.

A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the oxazolidinone moiety as a novel polar head, and the nature of the hydrophobic tail has also been varied. Docking studies using the crystal structure of an agonist bound to the ligand binding domain of the PPARα receptor have been performed as a tool for their design. Suitable synthetic procedures have been developed, and compounds with different stereochemistries have been prepared. Evaluation of basal and ligand-induced activity proved that several compounds showed agonist activity at the PPARα receptor, thus validating the oxazolidinone template for PPAR activity. In addition, two compounds, 2 and 4, showed dual PPARα/PPARγ agonism and interesting food intake reduction in rats.

Central versus peripheral antagonism of cannabinoid CB1 receptor in obesity: effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist, in Zucker rats.

The endogenous cannabinoid system plays an important modulatory role in feeding behaviour and metabolism, acting at both central and peripheral levels. Chronic administration of cannabinoid CB(1) receptor antagonists has been found to be effective in experimental obesity. However, clinically available cannabinoid receptor antagonists are inverse agonists that can target CB(1) receptors located in both central circuits regulating appetite and motivation and in peripheral organs regulating metabolism and energy expenditure. This profile complicates understanding of cannabinoid CB(1) receptor blockade as a therapeutic strategy in obesity and metabolic disorders. This review aims to explore the relevance of both inverse agonism and peripheral cannabinoid receptor blockade on the beneficial actions of chronic cannabinoid receptor blockade, by comparing the actions of the reference antagonist/inverse agonist rimonabant and the newly designed drug LH-21. LH-21 is a triazol derivative and a neutral cannabinoid receptor antagonist; it has a poor penetration rate into the central nervous system. When given acutely it decreases food intake and enhances the anorectic actions of oleoylethanolamide, a feeding suppressant lipid that acts on peripheral sensory terminals in a similar way as rimonabant. Unlike rimonabant, chronic administration of LH-21 (3 mg/kg) reduces feeding but does not improve hypertriglyceridaemia or hypercholesterolaemia; nor does it reduce liver fat deposits in Zucker rats. These results suggest that the inverse agonism and/or the antagonism of central cannabinoid CB(1) receptors are necessary for the metabolic benefits of cannabinoid CB(1) receptor blockade, but not for the appetite reduction.

Cannabinoids and neuropathic pain.

After a brief overview of the endocannabinoid system (CB receptors, and endocannabinoids) and of the cannabinergic ligands, some general issues related to cannabinoids and pain are commented. Finally, the most important findings regarding cannabinoids and neuropathic pain are discussed in detail.

Novel bronchodilators: synthesis, transamination reactions, and pharmacology of a series of pyrazino[2,3-c][1,2,6]thiadiazine 2, 2-dioxides.

The synthesis, pharmacological evaluation, and structure-activity relationships of a new class of bronchodilator agents, derivatives of pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides are described. The compounds were prepared by reaction of 3,4,5-triamino-1,2, 6-thiadiazine 1,1-dioxide with suitable 1,2-dicarbonyl compounds or alpha-hydroxyiminoketones and subsequent N-alkylation. A transamination procedure for synthesizing derivatives with different substituents at the 4-amino group is reported for the first time. The pyrazino[2,3-c][1,2,6]thiadiazine derivatives were screened for tracheal relaxing activity in vitro, and the active compounds were evaluated in vivo in guinea pigs as bronchodilator agents in comparison to theophylline. Among the compounds studied, the most interesting properties were displayed by the 4-amino-1-ethyl-6-methyl derivative (21). The toxicological evaluation of this derivative is also reported.

New aromatic iminoimidazolidine derivatives as alpha1-adrenoceptor antagonists: a novel synthetic approach and pharmacological activity.

The design, synthesis and alpha1-adrenoceptor antagonism of a series of bis-imidazoline (1a, 2a, 3a and 4a) and bis-guanidine (1b, 2b, 3b and 4b) diphenyl derivatives are reported. All of these compounds fulfill the conditions of the most recent pharmacophore proposed for alpha1-adrenoceptors and found in the literature. Besides, a novel synthetic approach to the preparation of 2-(arylimino)imidazolidine derivatives is described. All the tested compounds, except the bis-guanidinium derivative 3b, inhibit the contractile responses induced by noradrenaline in aortic rings of rat and rabbit in a dose-dependent manner. Our results indicate that, even though some discrepancies are observed in terms of the alpha1 subtype targeted by this new family of compounds, they show an interesting profile as antagonists of alpha1-adrenoceptors and a new prototype, compound 1a, has been found deserving further development.

Novel arylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides as platelet aggregation inhibitors. 2. Optimization by quantitative structure-activity relationships.

In the previous paper (Part 1), we described the synthesis and antiplatelet activity of a series of phenyl- and heteroarylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides. In this paper, we report the optimization of the platelet aggregation inhibitory activity by an iterative sequence of quantitative structure-activity relationship studies which encompassed synthesis and evaluation of the effects of structure variations at the 1-, 6-, and 7-positions of the heterocyclic system. A model has been established that correctly correlates antiplatelet activity in this series with the partial atomic charges calculated by a local density functional ab initio method. As a result of this study, the experimental platelet aggregation inhibitory activity of the lead compound was improved 300-fold.

Novel arylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides as inhibitors of platelet aggregation. 1. Synthesis and pharmacological evaluation.

A series of N-1-substituted derivatives of pyrazino[2,3-c][1,2, 6]thiadiazine 2,2-dioxides bearing aryl groups at the pyrazino moiety have been prepared. The synthesis involves ring formation between the diaminothiadiazine and suitable dicarbonyl compounds and subsequent introduction of the substituent at N-1. The compounds have been tested in vitro, as inhibitors of rabbit and human platelet aggregation, and ex vivo against rat platelet aggregation induced by arachidonic acid, ADP, collagen, U46619, and I-BOP. The results obtained indicate that some pyrazino[2,3-c][1,2, 6]thiadiazine derivatives show significant platelet aggregation inhibition similar to other antithrombotic agents and that the antiplatelet properties may be mediated by interference with the arachidonic acid pathway.

Molecular modeling of (E)-1-alkyl-4(3)-[2-(1H-azolyl)vinyl]-pyridinium salts and evaluation of their behavior towards choline acetyltransferase.

A new type of extended pi-system aza-analogue of (E)-4-[2-(1-naphthylvinyl)]-1-substituted pyridinium salts (NVP+) has been designed and its inhibitory activity towards choline acetyltransferase (ChAT) has been evaluated in vitro. Among the several examples of the title quaternary salts synthesized 2 and 3, the indolylvinylpyridinium salt 2e is the only one to show a very low ChAT inhibition. The molecular modeling study is highly illustrative of their behavior towards ChAT and interaction with the recognition site. Thus, several selected cations together with the reference NVP+ compound 1a were studied at the PM3 and AM1 levels respectively. At the global minima, all the compounds are planar, which, from the electron charge distribution, shows a degree of polarization similar to the NVP+ model compound 1a. However, the fitting of all optimized structures indicated that only the indole derivative 2e showed the same aromatic fragment orientation as 1a, which allows us to define a volume that is not accessible to ligands in the enzyme and consequently to a refined model of the choline acetyltransferase recognition site.

Heterocyclic structures useful in medicinal chemistry: the case of pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide.

Different aspects of a particular kind of heterocycle, namely pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide are discussed. These include synthesis, reactivity, tautomerism and acid-base properties, results of x-ray analysis and molecular orbital calcultations. Besides, some of the derivatives have shown interesting biological effects, among which are the diuretic properties which are also presented.

New 1,2,6-thiadiazine dioxide acyclonucleosides: synthesis and antiviral evaluation.

New acyclonucleosides derived from 1,2,6-thiadiazine dioxide systems have been synthesized. Lipase-mediated deacylation procedure was used to obtain the deprotected derivatives. All the newly prepared compounds were tested as antiviral agents, but none of them showed significant activity.

Synthesis and antimicrobial evaluation of new derivatives of diphenylsulfone.

New derivatives of diphenylsulfone have been synthesized and their antibacterial and antifungal activities evaluated. Their chemical structures have been established by means of analytical and NMR spectroscopic data.

N-substituted pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides. A new class of diuretics.

The synthesis and evaluation of a new class of diuretic agents derived from the pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide ring system are described. Preliminary structure-activity relationships indicate that the nature and location of the substituents at different positions of the heterocycle are crucial for activity. Thus, a novel synthetic methodology has been developed to selectively introduce the desired substituents at different positions. From the study of the pharmacological properties (dose-response curves, duration of action, and acute toxicity) of the most active compounds, 4-amino-1,7-diethyl-6-methylpyrazino[2,3-c][1,2,6]thiadiazine++ + 2,2-dioxide (9) was selected for further investigation. Compound 9 (C10H15N5O2S) crystallizes in space group P21/a with unit cell dimensions a = 16.482 (1), b = 9.3484 (3), c = 8.333 (3) A, beta = 103.003 (3) degrees, Z = 4.

Synthesis and biological screening of aminothiadiazine dioxides related to trimethoprim.

New derivatives of 3-amino-1,2,6-thiadiazine 1,1-dioxide have been synthesized and their antibacterial, antifungal and DHFR inhibitory activities evaluated. Their chemical structures have been established by means of analytical and NMR spectroscopic data. Among the compounds studied, the 4,4-dibromo derivative 11 showed fungistatic activity against C. albicans.

Potential histamine H2-receptor antagonists. Synthesis, conformational studies and activity of novel 3-oxo-1,2,5-thiadiazole 1,1-dioxide derivatives.

New histamine H2-receptor antagonists bearing a novel "urea equivalent", the 3-oxo-1,2,5-thiadiazole 1,1-dioxide ring, have been synthesized in a transamination reaction. Open chain derivatives have also been obtained. Theoretical conformational analysis of the compounds has been carried out using a molecular modelling program. Semiempirical CNDO/2 calculations have also been performed. The antisecretory and cytoprotective activities of the compounds have been evaluated.

A structure-reactivity study of the binding of acetylglutamate to carbamoyl phosphate synthetase I.

The requirements for binding at the N-acetyl-L-glutamate binding site of carbamoyl phosphate synthetase I were studied by the displacement of the activator from the central enzyme complex by analogs. Two carboxyls are essential and the acetamido group, if linked to the alpha-carbon, enhances binding 5000-fold. The subsite for the delta-carboxyl is mobile with respect to that for the alpha-carboxyl. Mixtures of complementary fragment of acetylglutamate do not bind, indicating a strong 'chelate' effect. Substituents revealed the existence of steric constraints around the delta-carboxyl, the alpha and gamma-carbons, and the whole of the acetamido group. However, phenyl substituents at the beta-carbon did not hamper binding, indicating that substituents at the beta-carbon face the solution. This is consistent with binding of acetylglutamate as the minimum-energy conformer. All analogs binding with high affinity are activators. Some analogs that bind poorly are competitive inhibitors. They appear to bind preferentially to a low-affinity conformation adopted by the site when the products dissociate and the substrates bind. The acetamido group plays no role in the binding of the inhibitors but it is crucial for the binding of the activators, and the high- and low-affinity conformations of the site differ markedly in structural selectivity.

Conformation-activity relationship in hexapeptides related to substance P.

Two hexapeptides related to the undecapeptide substance P (SP) Glu-Phe-Phe-Gly-Leu-Met-NH2 and Glu-Phe-Phe-Pro-Leu-Met-NH2, have been synthesized and their selectivity for the SP receptors studied. Conformational analyses of both peptides have been carried out using a molecular modeling program. Activity appears to be related to the adoption of a U-shape conformation since the Pro9 containing peptide in which this folding is favoured is much more active than the hexapeptide containing Gly9. Moreover, such a substitution induces a significant selectivity for the SP-P receptor compared to the SP-E receptor.

3,5-Diamino-1,2,6-thiadiazine 1,1-dioxide derivatives: synthesis and antiparasitic activity.

The synthesis of new 3,5-diamino-1,2,6-thiadiazine 1,1-dioxide derivatives is described and their structures discussed on the basis of 1H and 13C-N.M.R. data. The antiparasitic activity of these and related compounds was evaluated. The bacterial mutagenicity of the parent compound (I) was studied.