Fraction Lipophilicity Index (FLI). A drug-like metric for orally administered ionizable drugs.

Fraction Lipophilicity Index (FLI) was developed as a metric for assessing drug likeness of ionizable oral drugs. Considering that both log P and log D have distinct roles in drug action, the metric FLI allocates lipophilicity to a pH dependent neutral fraction of the molecule and is a weighted combination of log P and log D. It is expressed by equation: FLI = 2 x log P-│log D│. A dataset of 368 basic and acidic drugs was analyzed. Based on available % absorption data, drugs were classified into class 1 (268 drugs) and class 2 (100 drugs). The freeware MedChem Designer was used for log P and log D calculations at pH 7.4 and pH 5.5 for acids. Based on class 1, a drug-like FLI range 0-8 was defined. FLI distribution for class 2 is shifted towards significantly lower values. Comparison of FLI with rule of 5 (Ro5) shows that it leads to fewer values outside the established range than the corresponding log P violations for class 1. For class 2 it gives more alerts than Ro5 and can be considered complementary to Ro5, while it also sets lower limits to discriminate drugs with poor absorption.

RAGE: a multi-ligand receptor unveiling novel insights in health and disease.

Receptor for advanced glycation end products (RAGE) is expressed in a range of cell types such as endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons. It is a multi-ligand receptor and a member of the immunoglobulin superfamily of cell surface molecules. Its repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterin and S100/calgranulins. This variety of ligands allows RAGE to be implicated in a wide spectrum of pathological conditions such as diabetes and its complications, Alzheimer's disease, cancer and inflammation. Additionally, genetic polymorphisms in the RAGE gene may have impact on the functional activity of the receptor. It becomes obvious that RAGE pathway is a complicated one and the question of whether blockade of RAGE is a feasible and safe strategy for the prevention/treatment of chronic diseases is gradually gaining the attention of the pharmaceutical community. In this review the biology of RAGE and the triggered signaling cascades involved in health and disease will be presented. Additionally, its potential as an attractive pharmacotherapeutic target will be explored by pointing out the pharmacotherapeutic agents that have been developed for RAGE blockade.

The aldose reductase inhibitory capacity of Sorbus domestica fruit extracts depends on their phenolic content and may be useful for the control of diabetic complications.

Aldose reductase (ALR2) is a rate-limiting enzyme in the polyol pathway associated with the conversion of glucose to sorbitol and whose activity is implicated in the development of the long-term diabetic complications. Upon previous years, several scientific efforts were focused towards the development of ALR2 inhibitors as effective secondary anti-diabetic drugs. To this regard and during our extensive phytochemical analysis of Sorbus domestica (fam. Rosaceae), twenty nine different extracts, fractions and residues of five different maturity stages of Sorbus domestica fruits were evaluated for their in vitro ALR2 inhibitory capacity. The data obtained thus far have indicated that the diethyl ether and ethyl acetate fractions possess high aldose reductase inhibitory activity. Furthermore, detailed phytochemical LC-DAD-MS (ESI+) analysis of such extracts has shown that this aldose reductase inhibitory activity could be attributed to the high content of flavonoids and hydroxycinnamoyl esters. These results suggest that Sorbus domestica fruit consumption may be a promising way for lowering the incidence of long-term complications of diabetes mellitus, especially at early stages, a possibility being discussed in this paper.

Acute hemodynamic effects of moderate doses of nebivolol versus metoprolol in patients with systolic heart failure.

OBJECTIVES: To determine the acute hemodynamic effect of moderate doses of nebivolol (vasodilating beta1-selective blocker) vs. metoprolol tartrate (non-vasodilating beta1-selective blocker) in systolic heart failure (SHF). MATERIAL AND METHODS: 20 stable patients with SHF (left ventricular (LV) ejection fraction < or = 35%) underwent right heart catheterization. Once a reproducible baseline was obtained, patients were randomized to 5 mg nebivolol PO (n = 10) or metoprolol tartrate 50 mg PO (n = 10). Hemodynamic studies were repeated hourly for the first 4 hours and at 6 hours. RESULTS: Both agents caused bradycardia. Nebivolol caused additionally a decrease in systemic vascular resistance (SVR) and no significant change in pulmonary capillary wedge pressure (PCWP), and cardiac output (CO). In contrast, metoprolol caused a deterioration of LV systolic function characterized by a decrease in cardiac output, and an increase in SVR and PCWP. CONCLUSIONS: Treatment initiation with moderate doses of nebivolol is not associated with the adverse hemodynamic effects of metoprolol in patients with SHF. These findings suggest that a long up-titration period may not be necessary with nebivolol.

Modelling of aldose reductase inhibitory activity of pyrrol-1-yl-acetic acid derivatives by means of multivariate statistics.

The inhibition of the aldose reductase enzyme (AR) is considered to be a promising approach to control chronic diabetes complications as well as a number of other pathological conditions. Thus considerable efforts are devoted to the development of aldose reductase inhibitors (ARIs) as possible pharmacotherapeutic agents. The establishment of adequate QSAR models would serve to this purpose. In the present study multivariate statistics was applied in order to analyse the AR inhibitory activity data of twenty three pyrrol-1-yl-acetic acid derivatives on the basis of essential molecular descriptors. The compounds contain one or two carbonyl keto groups, which serve as a bridge to link the pyrrole moiety to aromatic nuclei with or without further substitution. An adequate one component model with satisfactory statistics was obtained and validated for its robustness and predictive ability. The influence of the different descriptors in ARI activity is discussed. The derived model was further used to predict the activity of four independent compounds and the contribution of their specific structural characteristics in ARI activity was evaluated.

Synthesis of [5-(4-pyrrol-1-yl-benzoyl)-1 H-pyrrol-2-yl)]-acetic acid and in vitro study of its inhibitory activity on aldose reductase enzyme and on protein glycation.

[5-(4-Pyrrol-1-yl-benzoyl)-1H-pyrrol-2-yl)]-acetic acid was synthesized in a Vilsmeier-Haack process and by other methods. The compound was found to inhibit the enzyme aldose reductase as well as the glycation process of proteins and could therefore be useful for the treatment of various pathological conditions.

The natural history of aneurysmal coronary artery disease.

OBJECTIVE: To assess the contribution of coronary artery ectasia, either isolated or in association with obstructive coronary artery disease, to morbidity and mortality from ischaemic heart disease. DESIGN: A retrospective study of patients undergoing coronary arteriography at a tertiary cardiac centre. PATIENTS AND METHODS: The epidemiological, clinical, arteriographic, and follow up characteristics of three groups of patients were examined: group A, 172 patients with coronary artery ectasia and coexisting significant coronary artery disease; group B, 31 patients with coronary artery ectasia only; group C, 165 patients with significant coronary artery disease but without ectasia, matched for sex and age with group A. RESULTS: Group A patients had a similar incidence of a previous myocardial infarction to group C patients (61.6% v 64.2%), exercise performance, severity of obstructive lesions (CASS score 2.19 v 2.14), and similar distribution of diseased vessels. At follow up of approximately two years they experienced a similar incidence of unstable angina (7.5% v 4.4%) and myocardial infarction plus cardiac death (4.9% v 6.1%). They underwent bypass surgery with similar frequency (39% v 42%) but there was a lower frequency of percutaneous transluminal coronary angioplasty (5.8% v 17%, P < 0.01). Patients with pure coronary ectasia (group B) had a lower incidence of a previous myocardial infarction (38.7%, 12/31, P < 0.05) than the two other groups. The infarct in all cases was related to an ectatic artery. Their exercise performance and ejection fraction (9 (SD 3) minutes and 56.5(9)%) were higher (P < 0.01) than group A (5 (2) minutes, 48.3(10)%) and group C (5.3 (2) minutes, 49.3(10)%). Group B had no myocardial infarctions, cardiac death, surgery, or intervention at follow up; 4.4% (5/115) developed unstable angina. The incidence of angina at study entry was similar in all three groups (38.7-49.7%). CONCLUSIONS: Coronary artery ectasia does not confer added risk in patients with coexisting obstructive coronary artery disease. Although there is a measurable incidence of previous myocardial infarction, patients with pure ectasia have a good prognosis. The wisdom of giving oral anticoagulants to such patients is questioned.

Synthesis, antioxidant and anti-inflammatory activity of novel substituted ethylenediamines and ethanolamines. A preliminary quantitative structure-activity relationship study.

Six substituted oxo- or hydroxy-aminoethanols and ethylenediamines were synthesized and tested as anti-inflammatory agents. 1-Substituted 4-(2-aminoethylamino)-1-butanones and 1-substituted 4-(2-hydroxy-ethylamino)-1-butanones were prepared by reacting the appropriate 4-chloro-1-butanone with the corresponding aminoalcohol or ethylenediamine. 1-Substituted 4-(2-aminoethylamino)-1-butanols were prepared by the reduction of the ketones with NaBH4 or NaBH3CN. The RM values of the synthesized compounds were determined as an expression of their lipophilicity. The effect of these compounds on in vitro non-enzymatic lipid peroxidation, their hydroxyl radical scavenging activity and their ability to interact with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH) were studied. The effect of the synthesized compounds on inflammation, using the carrageenan induced rat paw edema model was studied. Both anti-inflammatory and antioxidant activities depended on some structural characteristics of the synthesized compounds. It was also attempted to correlate the above mentioned activities with some physicochemical parameters using a quantitative structure-activity relationship approach. The primary amino group appeared to be of importance for antioxidant activity in this series of compounds.

Synthesis of GABA-valproic acid derivatives and evaluation of their anticonvulsant and antioxidant activity.

The synthesis and the anticonvulsant activity of a number of GABA and valproic acid derivatives are reported. The lipophilicity of these compounds and their inhibitory effect on lipid peroxidation were also investigated, in an effort to correlate the anticonvulsant activity with lipophilicity and inhibitory effect on lipid peroxidation. The synthesized compounds exhibited anticonvulsant effects which were stronger for the more lipophilic derivatives. One of the active anticonvulsants showed appreciable antioxidant properties. Finally, a good correlation was found between the experimentally derived (RM) and calculated (sigma f and log PSK) lipophilicity for this series of compounds.

Novel 1,4 substituted piperidine derivatives. Synthesis and correlation of antioxidant activity with structure and lipophilicity.

A series of novel piperidine derivatives was prepared and their lipophilicity was determined (as RM values). These compounds as well as two intermediate alpha-keto-esters were tested for antioxidant activity. It was found that the cysteamine derivatives were efficient antioxidants, i.e. they could inhibit lipid peroxidation, act as hydroxyl radical scavengers and interact with 2,2-diphenyl-1-picrylhydrazyl radicals. This interaction could be attributed to the free SH group and this activity seemed to be favoured by increased lipophilicity. Replacement of SH by NH2 or OH resulted in a decreased antioxidant activity of the compounds. However, the described activities seem not to be connected with any O2-.scavenging ability, at least under the experimental conditions applied. Furthermore, cysteamine derivatives seem to induce O2-.generation, a phenomenon often observed with thiol compounds. The antioxidant activity of the intermediate alpha-keto-esters varied and is probably mediated by different mechanisms.

Isomeric benzoylpyrroleacetic acids: some structural aspects for aldose reductase inhibitory and anti-inflammatory activities.

A number of isomeric benzoylpyrroleacetic acids (1-6) were prepared and tested in vitro for rat lenses aldose reductase activity. These pyrrole derivatives are structurally related to the acidic nonsteroidal anti-inflammatory drugs. Therefore, their anti-inflammatory properties were also evaluated in the carrageenan-induced rat paw edema model. Inhibition of the aldose reductase enzyme was found to depend on the presence of both the benzoyl and acetic acid functionalities. Better activity resulted when these moieties were introduced at positions 1 and 3 of the pyrrole ring. However, for anti-inflammatory activity, the acetic acid group was not necessary and, in some cases, its presence resulted in a loss of activity. 3-Benzoylpyrrole-1-acetic acid (6) exhibited an IC50 of 2.5 microM in the aldose reductase assay which is comparable to that of alrestatin (1.5 microM). Compound 6, however, showed no anti-inflammatory activity at doses up to a 100 mg/kg, ip, in the rat paw model.

Effect of aminoethylpyrroles on carrageenan-induced inflammation and on lipid peroxidation in rats: some structural aspects.

Nine 3-(2-aminoethyl)pyrrole derivatives were investigated as anti-inflammatory agents in the carrageenan-induced rat paw oedema model and as antioxidants in the non-enzymatic lipid peroxidation assay. It was found that the derivatives which were substituted with a p-toluenesulphonyl group exhibited considerable anti-inflammatory activity and some also showed antioxidant properties. However, the presence of a p-toluenesulphonyl group did not invariably lead to activity. A structural feature which was essential for both activities was the aminoethyl side chain. Although a relationship between the antiinflammatory and the antioxidant activities was not apparent, the combination of these properties could be useful.

Effect of some novel ethylenediamine and ethanolamine derivatives on carrageenan-induced inflammation. Correlation with antioxidant activity and structural characteristics.

The effect of eight ethylenediamine and ethanolamine derivatives on inflammation was investigated in the carrageenan-induced rat paw edema model. The ability of these compounds to inhibit superoxide anion radical (O2-.) formation in vitro was also examined using the xanthine-xanthine oxidase system. Almost all of these substances were found to possess anti-inflammatory activity. This action can be well correlated with their reported capacity to inhibit microsomal membrane lipid peroxidation, while they demonstrated negligible effect on O2.- generation. The above actions appear to depend on some structural characteristics, particularly in the aromatic series of compounds.

Cu(II) complex of an estradiol derivative with potent anti-inflammatory properties.

In the present study, the A-ring of estradiol was converted to an acetylsalicylic structure which was further complexed with Cu(II). The aim was to combine the anti-inflammatory properties of estrogens with those of Cu(II) complexes. Key intermediate of the synthesis was 2-formyl-estradiol (2) which was prepared in quantitative yield through reaction of the phenoxymagnesium bromide of estradiol with formaldehyde in the presence of HMPA. For a successful reaction, an excess of ethylmagnesium bromide was required, and the mechanism is discussed. The target complex 5 exhibited potent anti-inflammatory properties, comparable to those of indomethacin, in the carrageenan-induced rat paw edema. This biological activity was not due either to the steroidal ligand or to the complexed Cu(II) alone.

Effect of the position of the cyano-group of cyanopregnenolones on their drug metabolic inducing activity.

The effect of the position of the cyano-group of several cyanopregnenolones on the body's resistance to drugs and on drug metabolism was investigated. Female rats were pretreated with 2 alpha-, 6-, 16 alpha-, 17 alpha-cyano- or 16 alpha-cyanomethyl-pregnenolone or with pregnenolone, and the (in vivo) resistance to zoxazolamine, digitoxin and indomethacin, as well as the in vitro drug metabolism (post mitochondrial fraction) of zoxazolamine and ethylmorphine were determined. It was found that the 16-derivative was the most active in this respect, the 2- and 17-cyanopregnenolones were less active but significantly potent compared to controls, while the 6-cyano, the 16-cyanomethyl derivatives and pregnenolone were essentially inactive. These differences were explained in terms of an effective or poor fit of the steroids to their receptor. The poor performance of pregnenolone-16 alpha-acetonitrile was attributed to electronic effects. A hypothesis of some structural features of the receptor site for its interaction with the cyanopregnenolone inducers was presented.

Synthesis of 2-, 4- and 5-benzoylpyrrole-3-acetic acids and study of their in vitro effects on active oxygen species.

The isomeric benzoylpyrrole-3-acetic acids 2a-4a were synthesized on the basis of the known biological interest of analogous pyrrole-1- and pyrrole-2-acetic acids. The electrophilic benzoylation of ethyl pyrrole-2-acetate was found to give mixtures of the three substituted on the carbon atoms of the pyrrole ring isomers 2-4 in ratios which varied with the employed conditions. Experimental procedures were developed for the preferential formation of each one of the isomers in synthetically useful amounts. The involvement of the synthesized compounds in active oxygen intermediates was tested in vitro by examining their effect on lipid peroxidation using heat inactivated rat hepatic microsomes, and as hydroxyl radical scavengers, by determining the inhibition of formaldehyde production from the oxidation of DMSO. For comparison, some ESR spectra were recorded. It was found that 3 moderately inhibited lipid peroxidation, while all derivatives tested were potent hydroxyl radical scavengers. It is proposed that the reported compounds could find useful applications as protective agents against oxygen toxicity.

Lipophilicity of some substituted morpholine derivatives synthesized as potential antinociceptive agents.

Some substituted 2-alkoxy-morpholines have been synthesized as potential antinociceptive agents. These compounds share some structural characteristics of the piperidine analgesics. Their lipophilicity, expressed as log P (octanol-water) and as RM values (from reversed phase thin layer chromatography) was determined. Correlation of these two lipophilicity parameters indicated the classification of the tested compounds into two subgroups. Acute toxicity and, for some selected structures, analgesic activity are reported.