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Jean-Michel Dogné

Publications and source records attributed to Jean-Michel Dogné.

At least 19 recordsLinked to original sources
PubMed2006

Structure-based pharmacophore of COX-2 selective inhibitors and identification of original lead compounds from 3D database searching method.

A four-point pharmacophore of COX-2 selective inhibitors was derived from a training set of 16 compounds, using the Catalyst program. It consists of a H bond acceptor, two hydrophobic groups and an aromatic ring, in accordance with SAR data of the compounds and with topology of the COX-2 active site. This hypothesis, combined with exclusion volume spheres representing important residues of the COX-2 binding site, was used to virtually screen the Maybridge database. Eight compounds were selected for an in vitro enzymatic assay. Five of them show COX-2 inhibition close to that of nimesulide and rofecoxib, two reference COX-2 selective inhibitors. As a result, structure-based pharmacophore generation was able to identify original lead compounds, inhibiting the COX-2 isoform.

Binding Sites↗
PubMed2006

Targeting tumor-associated carbonic anhydrase IX in cancer therapy.

Carbonic anhydrase isoform IX (CA IX) is highly overexpressed in many types of cancer. Its expression, which is regulated by the HIF-1 transcription factor, is strongly induced by hypoxia and correlates with a poor response to classical chemo- and radiotherapies. CA IX contributes to acidification of the tumor environment by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons, thereby leading to acquisition of metastatic phenotypes and chemoresistance to weakly basic anticancer drugs. Inhibition of this enzymatic activity by specific inhibitors, such as the sulfonamide indisulam, reverts these processes, establishing a clear-cut role for CA IX in tumorigenesis. Thus, selective CA IX inhibitors could prove useful for elucidating the role of CA IX in hypoxic cancers, for controlling the pH imbalance in tumor cells and for developing diagnostic or therapeutic applications for tumor management. Indeed, fluorescent inhibitors and membrane-impermeant sulfonamides have recently been used as proof-of-concept tools, demonstrating that CA IX is an interesting target for anticancer drug development.

Animals↗
PubMed2006

Solid lipid microparticles as a sustained release system for pulmonary drug delivery.

The controlled release of drugs for pulmonary delivery is a research field which has been so far rather unexploited but is currently becoming increasingly attractive. The introduction part of this research article first details the potential advantages of solid lipid microparticles (SLMs) as drug carrier compared to liposomes and polymeric microspheres. The aim of this work is to use SLMs to impart a sustained release profile to a model drug, salbutamol acetonide (SA). SA was synthesized from salbutamol in order to increase the lipophilicity of this molecule and thereby to increase its incorporation efficiency into SLMs. SA-loaded SLMs were then produced by a hot emulsion technique followed by high-shear homogenisation and the manufacturing parameters were optimized using the experimental design methodology in order to reach a suitable particle size for pulmonary administration. Scanning electron micrographs showed that SLMs are spherical, have a smooth surface and that SA crystallizes outside of the particles when the drug loading is higher than 20%. This was confirmed by X-ray diffraction. SA in vitro release study from SLMs showed that the release rate increased with SA loading but remained in every case lower than the dissolution rate of pure SA.

Administration, Inhalation↗
PubMed2006

Synthesis and pharmacological evaluation of novel nitrobenzenic thromboxane modulators as antiplatelet agents acting on both the alpha and beta isoforms of the human thromboxane receptor.

Thromboxane A(2) (TXA(2)) is an arachidonic acid metabolite involved in pathologies such as stroke, myocardial infarction, and atherosclerosis. Consequently, the design of TXA(2) receptor (TP) antagonists remains of great interest in cardiovascular medicine. The actions of TXA(2) are mediated by its specific G-protein coupled receptor of which two alternative spliced isoforms, TPalpha and TPbeta, have been described in humans. In this study, we report the synthesis of a series of original N-alkyl-N'-[2-(cycloalkyl, alkylaryl)-5-nitrobenzenesulfonyl]urea and N-alkyl-N'-[2-(alkylaryl)-5-nitrobenzenesulfonyl]-N' '-cyanoguanidines and outline their pharmacological evaluation using the individual TPalpha and TPbeta isoforms. Among compounds analyzed, several of them exhibited greater affinity and/or functional activity for either TPalpha or TPbeta. The most promising molecules were also found to be antiplatelet agents. From the present results, structural features involved in isoform selectivity can be proposed, and thereby several lead compounds have been identified for the further development of selective TP isoform antagonists.

Adult↗
PubMed2006

Evaluation of original dual thromboxane A2 modulators as antiangiogenic agents.

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A(2) (TXA(2)) inhibitors derived from torasemide, a marketed loop diuretic with TXA(2) antagonistic properties, by evaluating their effects on human endothelial cell migration, adhesion, and viability in vitro, as well as in the ex vivo rat aortic ring assay. All drugs tested exhibited a marked affinity toward human platelet TXA(2) receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA(2) receptor agonist, and inhibited platelet TXA(2) synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA(2) inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelial growth factor (VEGF) as a chemoattractant but failed to affect cell adhesion and viability. The highest rates of cell migration inhibition were obtained with original compounds BM-567 and BM-573 (50.3 and 59.4% inhibition, respectively) when used at the final concentration of 10 microM. In addition, pretreatment of endothelial cells with these two drugs significantly prevented U-46,619-induced intracellular Ca(2+) pool mobilization, thus suggesting a mechanistic link between inhibition of the TXA(2) pathway and reduced endothelial cell migration. Treatment of rat aortic explants with U-46,619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F(2)) significantly enhanced vessel sprouting whereas aortic rings treated with some of the compounds, including BM-567 (N-n-pentyl-N'-[2-(cyclohexylamino)-5-nitrobenzenesulfonyl]urea) and BM-573 (N-tert-butyl-N'-[5-nitro-2-p-toluylaminobenzenesulfonyl]urea), showed a significant decrease in vessel sprouting, which was not reversed by the addition of VEGF. These data suggest that our original dual TXA(2) inhibitors bear antiangiogenic properties, mainly by inhibiting endothelial cell migration.

Angiogenesis Inhibitors↗
PubMed2006

Indanesulfonamides as carbonic anhydrase inhibitors. Toward structure-based design of selective inhibitors of the tumor-associated isozyme CA IX.

Carbonic anhydrases are ubiquitous metalloenzymes which are involved in fundamental processes (i.e., acid-base regulation, respiration, calcification, etc.). The carbonic anhydrase isozyme IX becomes an interesting pharmacological target due to its overexpression in cancer and its absence in normal tissue. Therefore, several indanesulfonamides were synthesized and tested for their inhibition both against the human CA IX and against two other biologically relevant isozymes (CA I and II). Structure-activity relationships are discussed and point out different compounds for its selectivity and activity against CA IX. To establish preliminary hypothesis for the design of new isozyme-selective CA IX inhibitors, we conducted molecular modeling. We describe here the first human CA IX model built by homology with another CA isozyme already crystallized. Docking studies were performed to explore the binding mode of our indanesulfonamide derivatives.

Amino Acid Sequence↗
PubMed2006

Prostanoids as pharmacological targets in COPD and asthma.

COPD (Chronic Obstructive Pulmonary Disease) and bronchial asthma are two severe lung diseases which represent a major problem of world public health. Leukotrienes and prostanoids play an important role in the pathogenesis of pulmonary diseases. Prostanoids: prostaglandins (PGs) and thromboxane A2 (TXA2), the cyclooxygenase metabolites of arachidonic acid are implicated in the inflammatory cascade that occurs in asthmatic airways. Recently, the roles played by isoprostanes or prostaglandin-like compounds nonenzymatically generated via peroxidation of membrane phospholipids by reactive oxygen species, in particular F2-isoprostanes, in pulmonary pathophysiology have been highlighted. This article aims to provide an overview of the role of prostanoids and isoprostanes in the pathogenesis of COPD and asthma and to discuss the pharmacological strategies developed in prevention and/or treatment of these pathologies.

Animals↗
PubMed2006

Large-pore membrane hemofiltration increases cytokine clearance and improves right ventricular-vascular coupling during endotoxic shock in pigs.

Hemodynamic improvement in patients suffering from both septic shock and renal failure who received hemofiltration suggested that an extrarenal epuration technique could be of interest in patients with septic shock alone. However, most of the studies using continuous venovenous hemofiltration (CVVH) in this setting evidenced neither cytokine clearance nor significant reduction in their plasma level. Lack of significant clearance was explained in part by the small size of the membrane pores. Therefore, we investigated the effects of large-pore membrane hemofiltration (LPHF) during endotoxic shock in pigs on interleukin 6 (IL-6) and interleukin 10 (IL-10) clearances, and on right ventricular (RV)-vascular coupling. Thirteen anesthetized healthy pigs weighing 20-30 kg were divided into two groups. In the Endo group (n = 6), the pigs received a 0.5-mg/kg endotoxin infusion over a period of 30 mins from T0 to T30. In the EndoHF group (n = 7), LPHF (cutoff = 80 kDa) and an ultrafiltration rate of 45 mL/kg/h were started 30 mins after the end of the endotoxin infusion, from T60 to T240. In this model of porcine endotoxic shock, LPHF was responsible for a significant clearance of IL-6 (20 mL/min) and Il-10 (14 mL/min), and for an improvement in RV-vascular coupling.

Animals↗
PubMed2006

From the design to the clinical application of thromboxane modulators.

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2) (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. In the first part of this review, we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part, we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock, preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis.

Animals↗
PubMed2006

Coxibs and cardiovascular side-effects: from light to shadow.

Since the discovery of COX-2, a second subtype of cyclooxygenase, selective inhibitors or "coxibs" were developed with the idea that this isoform was inducible at the site of inflammation whereas COX-1 was expressed constitutively in several tissues including gastric epithelium. This new class of non steroidal anti-inflammatory agents was though to be safer for ulcerations of the gastroinstestinal mucosa observed with non selective COX-2 inhibitors. Nevertheless, at the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. This decision raised serious concerns about safety of selective COX-2 inhibitors which are actively marketed today, and the ones currently under development. The mechanism of this cardiovascular toxicity could lie in the inhibition of COX-2 itself, and thus be a class effect. On the other hand, these cardiovascular side effects could be limited on rofecoxib and be dependent on its chemical and/or pharmacological own properties. This hypothesis is undermined by the unexpected findings of one colon cancer study which has shown that celecoxib might also increase the chance of heart attack and stroke in some patients. In this review, we compared the different coxibs marketed to date on the basis of their clinical, pharmacological and chemical properties with the aim of providing some clues in the understanding of their potential or revealed "cardiovascular effects".

Animals↗
PubMed2006

Implications of the molecular basis of prostacyclin biosynthesis and signaling in pharmaceutical designs.

Prostacyclin (PGI(2)) is one of the major vascular protectors against thrombosis and vasoconstriction, caused by thromboxane A(2). Understanding the molecular mechanisms of PGI(2) biosynthesis and signaling is crucial to the development of therapeutic approaches to regulate PGI(2) functions. This review provides information regarding the most current advances in the findings of the molecular mechanisms for PGI(2) biosynthesis in the endoplasmic reticulum (ER) membrane through the coordination between PGI(2) synthase and its upstream enzymes, cyclooxygenase-1 (COX-1) or -2 (COX-2), and for PGI(2) signaling through its cell membrane receptors and nuclear peroxisome proliferator-activated receptors. The substrate presentation from the COXs to PGI(2) synthase and its cell membrane receptor/G protein coupling sites, as characterized by our group, are discussed in detail. The association between the regulation of the biosynthesis and signaling of PGI(2) with the pathophysiological processes of PGI(2)-related diseases is also discussed. The molecular knowledge of PGI(2) biosynthesis and signaling will help to design the next generation of drugs, specifically targeting the regulation of PGI(2) functions, which will undoubtedly provide advances in cardiovascular protection and the treatment of PGI(2)-related diseases.

Animals↗
PubMed2005

Thromboxane, prostacyclin and isoprostanes: therapeutic targets in atherogenesis.

Atherosclerosis is a chronic disease of the vasculature that is influenced by multiple factors that involve a complex interplay between some components of the blood and the arterial wall. Inflammation and oxidative stress have key roles in atherogenesis. The production of F2-isoprostanes (F2-IPs), thromboxane A2 (TxA2) and prostacyclin (PGI2) increases in atherosclerosis, and recent studies show that pharmacological modulation of their biosynthesis and biological activities are important therapeutic targets for managing atherosclerosis. In this review, we highlight recent breakthroughs in the roles of F2-IPs, TxA2 and PGI2 in atherogenesis, and identify pertinent therapeutic targets.

Animals↗
PubMed2005

A new potential cyclooxygenase-2 inhibitor, pyridinic analogue of nimesulide.

In this paper, the binding mode of original pyridinic compounds structurally related to nimesulide, a preferential cyclooxygenase (COX)-2 inhibitor, is analyzed by docking simulations in order to understand structure-activity relationships of this family. Structural modifications are proposed to reverse the selectivity of the more active inhibitor of the series characterized by a preferential activity on COX-1. On the basis of these modifications, a new compound with a bromo substituent was designed and showed a COX-2 selective inhibition.

Crystallography, X-Ray↗
PubMed2005

Effects of BM-573, a thromboxane A2 modulator on systemic hemodynamics perturbations induced by U-46619 in the pig.

The aim of our study was to evaluate the effects of thromboxane A2 (TXA2) agonist, U-46619, on systemic circulatory parameters in the pigs before and after administration of a novel TXA2 receptor antagonist and synthase inhibitor (BM-573). Twelve anesthetized pigs were randomly assigned in two groups: in Ago group (n=6), the animals received six consecutive injections of U-46619 at 30 min interval, while in Anta group (n=6) they received an increasing dosage regimen of BM-573 10 min before each U-46619 injection. The effects of each dose of BM-573 on ex vivo platelet aggregation induced by arachidonic acid, collagen or ADP were also evaluated. Vascular properties such as characteristic impedance, peripheral resistance, compliance, arterial elastance were estimated using a windkessel model. Intravenous injections of 0.500 mg/ml of BM-573 and higher doses resulted in a complete inhibition of platelet aggregation induced by arachidonic acid. In the same conditions, BM-573 completely blocked the increase of arterial elastance, and stabilized both mean aortic blood pressure and mean systemic blood flow. In conclusion, BM-573 could therefore be a promising therapeutic approach in pathophysiological states where TXA2 plays a main role in the increase of vascular resistance like in pathologies such as systemic hypertension.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2005

Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/membrane-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating hydrazino moieties.

Targeting proteins overexpressed in hypoxic tumors is as an important means of controlling cancer disease. One such protein is the carbonic anhydrase (CA) isoenzyme IX, which in some types of tumors is overexpressed 150-200-fold. We report here a series of sulfonamide derivatives, prepared from 2-carbohydrazido- and 4-carbohydrazido-benzenesulfonamides, which were further derivatized by reaction with aryl isocyanates or arylsulfonyl isocyanates. Several low nanomolar CA IX inhibitors were detected in this way. SAR is discussed for the diverse types of inhibitors and their affinity for different isozymes, with the aim of obtaining isozyme-specific CA IX inhibitors, with putative applications as antitumor drugs.

Antigens, Neoplasm↗
PubMed2005

Characterization of an original model of myocardial infarction provoked by coronary artery thrombosis induced by ferric chloride in pig.

BACKGROUND: Great advances have been made in the prevention of thrombotic disorders by developments of new pharmacological and surgical treatments. Animal models of arterial thrombosis have largely contributed to the discovery and to the validation of original treatments. The purpose of the present work was to develop and validate an original model of acute myocardial infarction provoked in pig by thrombosis of the left anterior descending (LAD) coronary artery induced by topical application of ferric chloride solution. METHODS AND RESULTS: Myocardial infarction, resulting from an occlusive and adherent mixed thrombus formed in the LAD coronary artery, was examined at macroscopic level using dual staining technique (Evans blue dye; triphenyltetrazolium chloride) and at microscopic level using conventional histological analyses and immunohistochemical detection of desmin. Biochemical markers (troponin T and ATP), platelet reactivity and standard hemodynamic parameters (such as stroke volume, ejection fraction, stroke work and cardiac output) have also been evaluated. From these analyses, it was demonstrated that each pig developed a transmural area of irreversible damage mainly located in the anteroseptal region of the left ventricle. The more progressive development of coronary artery occlusion, as compared to an abrupt ligation, was accompanied by a correspondingly progressive impairment in hemodynamics. CONCLUSION: We conclude that this original porcine model of myocardial infarction is quite close to clinical pathophysiological conditions, such as thrombus formation occurring after atherosclerotic plaque rupture. This certainly constitutes a further argument in favour of this model to assess pharmaceutical or mechanical support of an acutely ischemic heart.

Adenosine Triphosphate↗