Markus Rey

Actelion Pharmaceuticals Ltd, Allschwil, Basel-Landschaft, Switzerland

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Publications (21)56.19 Total impact

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    ABSTRACT: Recent post-hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenyl-pyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475. The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of ACT-246475 was low in rat and dog, we developed the bis-((isopropoxycarbonyl)oxy)methyl ester prodrug, ACT-281959. ACT-246475 is a novel, selective and reversible P2Y12 antagonist that showed efficacy in the rat ferric chloride thrombosis model, when administered intravenously as parent or orally as its prodrug ACT-281959. Moreover, ACT-246475 displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.
    No preview · Article · Nov 2015 · Journal of Medicinal Chemistry
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    ABSTRACT: We compared the efficacy of macitentan, a novel dual ETA/ETB receptor antagonist (ERA), to that of another dual ERA, bosentan, in a rat model of non-vasoreactive pulmonary hypertension with particular emphasis on right ventricular (RV) remodeling. Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive pulmonary hypertension characterized by absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg/kg/d), but not bosentan (300 mg/kg/d), significantly prevented pulmonary vascular remodeling, RV hypertrophy and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and HPLC analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue. Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophy in a model of non-vasoreactive pulmonary hypertension. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared to bosentan.This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivatives 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    Full-text · Article · Jul 2015 · Journal of cardiovascular pharmacology
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    ABSTRACT: Chemical evolution of mibefradil resulted in the identification of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. A SAR study, in vitro and in vivo DMPK properties as well as the in vivo antihypertensive effect in rats are presented. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Jul 2015 · Bioorganic & medicinal chemistry letters
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    ABSTRACT: The goal of this study was to characterize the role of Endothelin (ET) type B receptors (ETB) on vascular function in healthy and diseased conditions and demonstrate how it affects the pharmacological activity of ET receptor antagonists (ERAs). The contribution of the ETB receptor to vascular relaxation or constriction was characterized in isolated arteries from healthy and diseased rats with systemic (Dahl-S) or pulmonary hypertension (monocrotaline). Because the role of ETB receptors is different in pathological vis-à-vis normal conditions, we compared the efficacy of ETA-selective and dual ETA/ETB ERAs on blood pressure in hypertensive rats equipped with telemetry. In healthy vessels, ETB receptors stimulation with sarafotoxin S6c induced vasorelaxation and no vasoconstriction. In contrast, in arteries of rats with systemic or pulmonary hypertension, endothelial ETB-mediated relaxation was lost while vasoconstriction upon stimulation by sarafotoxin S6c was observed. In hypertensive rats, administration of the dual ETA/ETB ERA macitentan on top of a maximal effective dose of the ETA-selective ERA ambrisentan further reduced blood pressure, indicating that ETB receptors blockade provides additional benefit. Taken together these data suggest that in pathology, dual ETA/ETB receptor antagonism can provide superior vascular effects compared to ETA-selective receptor blockade.This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivatives 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    Full-text · Article · May 2015 · Journal of cardiovascular pharmacology
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    ABSTRACT: The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions despite the well-recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study we sought to identify genomic commonalities between the gene expression profiles obtained from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium and rat lungs harvested at days 3, 7, 14, 21, 28, 42 and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at day 7. At this point of maximal rat-human commonality we identified a novel set of twelve disease-relevant translational gene markers (C6; CTHRC1; CTSE; FHL2; GAL; GREM1; LCN2; MMP7; NELL1; PCSK1; PLA2G2A; SLC2A5) that was able to separate almost all IPF patients from controls in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with carbon monoxide (DLCO) measurements, four members of the translational gene marker set contributed to stratify IPF patients according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, TGF1-treated primary human lung fibroblasts and TGF1-treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model - human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions and thus facilitates the development of novel treatments in this devastating lung disease.
    No preview · Article · Jul 2014 · American Journal of Respiratory Cell and Molecular Biology
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    ABSTRACT: Aims The endothelin (ET) system is a tissular system, as the production of ET isoforms is mostly autocrine or paracrine. Macitentan is a novel dual ETA/ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade. To determine if these features translate into improved efficacy in vivo, a study was designed in which rats with either systemic or pulmonary hypertension and equipped with telemetry were given macitentan on top of maximally effective doses of another dual ETA/ETB receptor antagonist, bosentan, which does not display sustained receptor occupancy and shows less tissue distribution. Methods After establishing dose–response curves of both compounds in conscious, hypertensive Dahl salt-sensitive and pulmonary hypertensive bleomycin-treated rats, macitentan was administered on top of the maximal effective dose of bosentan. Key Findings In hypertensive rats, macitentan 30 mg/kg further decreased mean arterial blood pressure (MAP) by 19 mmHg when given on top of bosentan 100 mg/kg (n = 9, p < 0.01 vs. vehicle). Conversely, bosentan given on top of macitentan failed to induce an additional MAP decrease. In pulmonary hypertensive rats, macitentan 30 mg/kg further decreased mean pulmonary artery pressure (MPAP) by 4 mmHg on top of bosentan (n = 8, p < 0.01 vs. vehicle), whereas a maximal effective dose of bosentan given on top of macitentan did not cause any additional MPAP decrease. Significance The add-on effect of macitentan on top of bosentan in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy.
    Full-text · Article · Feb 2014 · Life sciences
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    ABSTRACT: In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P1 agonists such as the thiophene derivative 1. As a continuation of these efforts, we replaced the thiophene in 1 by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P1 agonists (e.g., 2) efficiently reducing blood lymphocyte count in the rat. Structural features influencing the compounds' receptor affinity profile and pharmacokinetics are discussed. In addition, the ability to penetrate brain tissue has been studied for several compounds. As a typical example for these pyridine based S1P1 agonists, compound 53 showed EC50 values of 0.6 and 352 nM for the S1P1 and S1P3 receptor, respectively, displayed favorable PK properties, and penetrated well into brain tissue. In the rat, compound 53 maximally reduced the blood lymphocyte count for at least 24 h after oral dosing of 3 mg/kg.
    Full-text · Article · Dec 2013 · Journal of Medicinal Chemistry
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    ABSTRACT: Previously, we reported on the discovery of a novel series of bicyclo[3.1.0]hexane fused thiophene derivatives that serve as potent and selective S1P1 receptor agonists. Here, we discuss our efforts to simplify the bicyclohexane fused thiophene head. In a first step the bicyclohexane moiety could be replaced by a simpler, less rigid cyclohexane ring without compromising the S1P receptor affinity profile of these novel compounds. In a second step, the thiophene head was simplified even further by replacing the cyclohexane ring with an isobutyl group attached either to position 4 or position 5 of the thiophene. These structurally much simpler headgroups again furnished potent and selective S1P1 agonists (e.g., 87), which efficiently and dose dependently reduced the number of circulating lymphocytes upon oral administration to male Wistar rats. For several compounds discussed in this report lymphatic transport is an important route of absorption that may offer opportunities for a tissue targeted approach with minimal plasma exposure.
    Full-text · Article · Dec 2013 · Journal of Medicinal Chemistry
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    ABSTRACT: From a high-throughput screening campaign aiming at the identification of novel S1P1 receptor agonists, the pyrazole derivative 2 emerged as a hit structure. Medicinal chemistry efforts focused not only on improving the potency of the compound but in particular also on resolving its inherent instability issue. This led to the discovery of novel bicyclo[3.1.0]hexane fused thiophene derivatives. Compounds with high affinity and selectivity for S1P1 efficiently reducing the blood lymphocyte count in the rat were identified. For instance, compound 85 showed EC50 values of 7 and 2880 nM on S1P1 and S1P3, respectively, had favorable pharmacokinetic properties in rat and dog, distributed well into brain tissue, and efficiently and dose dependently reduced the blood lymphocyte count in the rat. After oral administration to spontaneously hypertensive rats, the S1P1 selective compound 85 showed no effect on mean arterial blood pressure and affected the heart rate during the wake phase of the animals only.
    No preview · Article · Nov 2013 · Journal of Medicinal Chemistry
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    ABSTRACT: Ponesimod, a selective S1P1 receptor modulator, reduces the blood lymphocyte count in all tested species by preventing egress of T and B cells from thymus and peripheral lymphoid organs. In addition, ponesimod transiently affects heart rate and atrioventricular (AV) conduction in humans, effects not observed in mice, rats, and dogs with selective S1P1 receptor modulators, suggesting that the regulation of heart rate and rhythm is species dependent. In the present study, we used conscious guinea pigs implanted with a telemetry device to investigate the effects of single and multiple oral doses of ponesimod on ECG variables, heart rate, and blood pressure. Oral administration of ponesimod did not affect the sinus rate (P rate) but dose-dependently induced AV block type I to III. A single oral dose of 0.1 mg/kg had no effect on ECG variables, while a dose of 3 mg/kg induced AV block type III in all treated guinea pigs. Repeated oral dosing of 1 or 3 mg/kg ponesimod resulted in rapid desensitization, so that the second dose had no or a clearly reduced effect on ECG variables as compared with the first dose. Resensitization of the S1P1 receptor in the heart was concentration dependent. After desensitization had been induced by the first dose of ponesimod, the cardiac system remained desensitized as long as the plasma concentration was ≥75 ng/ml. By using a progressive up-titration regimen, the first-dose effect of ponesimod on heart rate and AV conduction was significantly reduced due to desensitization of the S1P1 receptor. In summary, conscious guinea pigs implanted with a telemetry device represent a useful model to study first-dose effects of S1P1 receptor modulators on heart rate and rhythm. This knowledge was translated to a dosing regimen of ponesimod to be tested in humans to avoid or significantly reduce the first-dose effects.
    Full-text · Article · Sep 2013 · PLoS ONE
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    ABSTRACT: S1P receptor agonists lead to sequestration of circulating lymphocytes to lymphoid organs and prevent these immune cells from causing inflammation and tissue damage. S1P receptor agonists therefore have great therapeutic potential to treat autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or psoriasis. Indeed, a pro-drug of a non selective S1P receptor agonist, FTY720 (GilenyaTM) is an approved treatment for relapsing remitting multiple sclerosis. Attention has focused on dissecting the pharmacological effects conveyed by the five known S1P receptors. Experiments with S1P1 receptor knock-out mice and S1P1 selective agonists demonstrated that targeting S1P1 is necessary and sufficient to cause lymphocyte sequestration to lymphoid organs. S1P5 agonism maintains immune quiescence in the brain and may contribute to remyelination, whereas activation of the S1P3 pathway has been reported to cause heart rate reduction, vaso- and bronchoconstriction, and pulmonary epithelial leakage. To date, a number of selective S1P1 and S1P1/5 receptor agonists are in clinical development for multiple sclerosis and other diseases. Despite being selective against S1P3, several of these compounds have been reported to cause first dose effects on heart rate in humans. Here, we will present our efforts to evolve the structure of our HTS hit 1 into a compound suitable for clinical development. Key questions driving our drug discovery program were the compounds’ stability, their S1P receptor selectivity profile as well as means to avoid the first dose effect on heart rate.
    No preview · Conference Paper · Apr 2013
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    ABSTRACT: Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ET(A) with significant affinity for the ET(B) receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.
    Full-text · Article · Aug 2012 · Journal of Medicinal Chemistry

  • No preview · Conference Paper · May 2012
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    Markus Rey · Edgar W Weber · Patrick D Hess
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    ABSTRACT: Here we evaluated the ability of a new, dual blood-pressure telemetry transmitter to simultaneously measure pulmonary and systemic blood pressure and the electrocardiogram in rats. The transmitter was implanted in normotensive and monocrotaline-induced pulmonary hypertensive Wistar rats, with sensing catheters placed in the pulmonary artery (channel 1) and descending aorta (channel 2). Biopotential electrodes were positioned to record an apex-based lead II electrocardiogram. Pulmonary and systemic arterial blood pressure and electrocardiographic waveforms were recorded between 2 and 12 wk after implantation of the transmitter. During this period, pulmonary arterial pressure progressively increased in monocrotaline-treated compared with saline-treated rats. The pharmacologic response of rats to reference compounds was measured by using the transmitter to validate the technique and to evaluate the ability of the device to transmit changes in blood pressure and the electrocardiogram. Validation against 2 Millar high-fidelity blood-pressure catheters confirmed the accuracy of the blood pressure data recorded with the transmitter. In addition, local tolerance of the associated catheters was confirmed by histologic examination.
    Preview · Article · Mar 2012 · Journal of the American Association for Laboratory Animal Science: JAALAS

  • No preview · Conference Paper · May 2011
  • Markus Rey · Patrick Hess · Martine Clozel
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a debilitating and often fatal disease characterized by a progressive increase in pulmonary vascular resistance that leads to right ventricular failure. Described in this unit is an in vivo model of monocrotaline-induced pulmonary hypertension in rats that can be used to assess the effects of antihypertensive agents on pulmonary artery pressure and right ventricular hypertrophy.
    No preview · Article · Sep 2009 · Current protocols in pharmacology
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    P Hess · M Rey · D Wanner · B Steiner · M Clozel
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    ABSTRACT: The pro-arrhythmic risk inherent to a new drug must be assessed at an early preclinical stage. Telemetry system implantation is a method widely used in vivo in various species. The present study was designed to assess whether conscious freely moving guineapigs can be used to predict QT prolongation in vivo. The guineapig has three advantages over the dog and the primate. First, it has specific ion channels similar to man; second, a smaller amount of test article is required for the investigation and third, its housing is less expensive. Under sterile conditions and isoflurane anaesthesia, telemetry transmitters were implanted intraperitoneally in male Dunkin Hartley guineapigs. Blood pressure, heart rate and electrocardiographic intervals were measured from two days up to eight months. Chronic implantation of the telemetry device did not lead to anatomic or macroscopic alterations in the abdominal cavity and no inflammation of the peritoneum or infection was observed. Four reference compounds were used: three positive (sotalol, terfenadine and dofetilide) and one negative reference (enalapril). Single oral administration of all three positive references dose-dependently induced bradycardia and QT corrected (QTc) prolongation. In contrast, neither enalapril nor its vehicle prolonged the QTc. These results demonstrate that the guineapig is both a suitable model and a good alternative to dogs or primates to assess the potential of compounds for QT interval prolongation in the early stages of drug development.
    Full-text · Article · Nov 2007 · Laboratory Animals
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    ABSTRACT: The dual endothelin receptor antagonist, bosentan, and the phosphodiesterase inhibitor, sildenafil, are efficacious in experimental and clinical pulmonary hypertension (PHT). The effects of bosentan, sildenafil, and their combination were evaluated in rats with monocrotaline (MCT)-induced PHT. A first group consisted of control rats with no MCT injection. Four other groups of rats received MCT subcutaneously and were assigned to receive no treatment, 300 mg/kg/day bosentan as food admix, 100 mg/kg/day sildenafil in drinking water, or their combination for 4 weeks. The doses of bosentan and sildenafil were the maximally effective doses based on a dose-range-finding study. Mortality was 0%, 53%, 11%, 11%, and 0%, respectively, in the five different groups. Bosentan and sildenafil significantly attenuated the increase in mean pulmonary arterial pressure, and the combination had an additional effect. Similarly, bosentan, sildenafil, and, to a greater extent, their combination significantly reduced right ventricular (RV) hypertrophy. Bosentan, but not sildenafil, decreased norepinephrine and BNP plasma concentrations, reduced kidney weight, and normalized systemic hemodynamics. In conclusion, bosentan and sildenafil are efficacious in rats with chronic PHT, and their combination shows an additional effect for decreasing pulmonary arterial pressure, reducing plasma catecholamines, maintaining body weight, and reducing mortality.
    No preview · Article · Jul 2006 · Experimental Biology and Medicine
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    ABSTRACT: Urotensin-II (U-II) is a cyclic peptide that acts through a specific G-protein-coupled receptor, UT receptor. Urotensin-II and UT receptors have been described in pancreas and kidney, but their function is not well understood. We studied the effects of chronic treatment of diabetic rats with the orally active selective U-II receptor antagonist palosuran. Streptozotocin treatment causes pancreatic beta-cell destruction and leads to the development of hyperglycemia, dyslipidemia, and renal dysfunction. Long-term treatment of streptozotocin-induced diabetic rats with palosuran improved survival, increased insulin, and slowed the increase in glycemia, glycosylated hemoglobin, and serum lipids. Furthermore, palosuran increased renal blood flow and delayed the development of proteinuria and renal damage. The U-II system is unique in that it plays a role both in insulin secretion and in the renal complications of diabetes. Urotensin receptor antagonism might be a new therapeutic approach for the treatment of diabetes.
    Preview · Article · Apr 2006 · Journal of Pharmacology and Experimental Therapeutics
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    ABSTRACT: Urotensin-II (U-II) is a cyclic peptide now described as the most potent vasoconstrictor known. U-II binds to a specific G protein-coupled receptor, formerly the orphan receptor GPR14, now renamed urotensin receptor (UT receptor), and present in mammalian species. Palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt) is a new potent and specific antagonist of the human UT receptor. ACT-058362 antagonizes the specific binding of (125)I-labeled U-II on natural and recombinant cells carrying the human UT receptor with a high affinity in the low nanomolar range and a competitive mode of antagonism, revealed only with prolonged incubation times. ACT-058362 also inhibits U-II-induced calcium mobilization and mitogen-activated protein kinase phosphorylation. The binding inhibitory potency of ACT-058362 is more than 100-fold less on the rat than on the human UT receptor, which is reflected in a pD'(2) value of 5.2 for inhibiting contraction of isolated rat aortic rings induced by U-II. In functional assays of short incubation times, ACT-058362 behaves as an apparent noncompetitive inhibitor. In vivo, intravenous ACT-058362 prevents the no-reflow phenomenon, which follows renal artery clamping in rats, without decreasing blood pressure and prevents the subsequent development of acute renal failure and the histological consequences of ischemia. In conclusion, the in vivo efficacy of the specific UT receptor antagonist ACT-058362 reveals a role of endogenous U-II in renal ischemia. As a selective renal vasodilator, ACT-058362 may be effective in other renal diseases.
    Full-text · Article · Nov 2004 · Journal of Pharmacology and Experimental Therapeutics