23 results on '"Delbeck M"'
Search Results
2. A novel mouse model reproducing pathomorphological and inflammatory hallmarks of COPD
- Author
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Reiter, B, primary, Bordag, N, additional, Schnoegl, D, additional, Bence, N, additional, Delbeck, M, additional, Kwapiszewska, G, additional, Cernecka, H, additional, Meding, J, additional, and Marsh, L M, additional
- Published
- 2022
- Full Text
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3. Antifibrotic and anti-inflammatory effects of the selective nonsteroidal MR antagonist finerenone in preclinical pulmonary fibrosis
- Author
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Delbeck, M, primary, Joseph, A, additional, Pitt, B, additional, and Kolkhof, P, additional
- Published
- 2021
- Full Text
- View/download PDF
4. Finerenone, a novel selective non-steroidal mineralocorticoid receptor antagonist with a balanced cardiorenal tissue distribution confers pronounced end organ protection at low natriuretic doses: 1047
- Author
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Kolkhof, P, Delbeck, M, Kretschmer, A, Steinke, W, Hartmann, E, Baerfacker, L, Eitner, F, Albrecht-Kuepper, B, and Schaefer, S
- Published
- 2014
5. Crystal Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor
- Author
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vonNussbaum, F., primary, Li, V.M., additional, Meibom, D., additional, Anlauf, S., additional, Bechem, M., additional, Delbeck, M., additional, Gerisch, M., additional, Harrenga, A., additional, Karthaus, D., additional, Lang, D., additional, Lustig, K., additional, Mittendorf, J., additional, Schaefer, M., additional, Schaefer, S., additional, and Schamberger, J., additional
- Published
- 2016
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- View/download PDF
6. Crystal Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor
- Author
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von Nussbaum, F., primary, Li, V.M., additional, Meibom, D., additional, Anlauf, S., additional, Bechem, M., additional, Delbeck, M., additional, Gerisch, M., additional, Harrenga, A., additional, Karthaus, D., additional, Lang, D., additional, Lustig, K., additional, Mittendorf, J., additional, Schaefer, M., additional, Schaefer, S., additional, and Schamberger, J., additional
- Published
- 2016
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7. Hämolyse und Hämoglobinadsorption durch Zinkverbindungen
- Author
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Delbeck, G. and Delbeck, M.
- Published
- 1973
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- View/download PDF
8. Crystal Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor
- Author
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vonNussbaum, F., primary, Li, V.M.-J., additional, Allerheiligen, S., additional, Anlauf, S., additional, Baerfacker, L., additional, Bechem, M., additional, Delbeck, M., additional, Fitzgerald, M.F., additional, Gerisch, M., additional, Gielen-Haertwig, H., additional, Haning, H., additional, Karthaus, D., additional, Lang, D., additional, Lustig, K., additional, Meibom, D., additional, Mittendorf, J., additional, Rosentreter, U., additional, Schaefer, M., additional, Schaefer, S., additional, Schamberger, J., additional, Telan, L.A., additional, and Tersteegen, A., additional
- Published
- 2015
- Full Text
- View/download PDF
9. Einfluss des neuen nichtsteroidalen Mineralocorticoid Antagonisten BR-4628 und des Mineralocorticoid Antagonisten Spironolacton auf die Fibroseentwicklung im BDL Modell der Ratte
- Author
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Schulte, S, primary, Kolkhof, P, additional, Strack, I, additional, Delbeck, M, additional, Kretschmer, A, additional, Drebber, U, additional, Toex, U, additional, and Steffen, HM, additional
- Published
- 2011
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10. Der Einfluss des neuen nichtsteroidalen Mineralocorticoid Antagonisten BR-4628 auf die Natriumausscheidung bei sekundärer biliärer Leberzirrhose
- Author
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Schulte, S, primary, Kolkhof, P, additional, Strack, I, additional, Demir, M, additional, Delbeck, M, additional, Kretschmer, A, additional, Drebber, U, additional, Goeser, T, additional, Töx, U, additional, and Steffen, HM, additional
- Published
- 2010
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11. Preclinical in vitro and in vivo evaluation of [ 11 C]ORM-13070 as PET ligand for alpha-2C adrenergic receptor occupancy using PET imaging in non-human primates.
- Author
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Piel I, Constantinescu CC, de la Puente Bethencourt D, Bonsall DR, Rabiner EA, Zasadny KR, Llopis Amenta A, Wells LA, Poethko T, Prange W, and Delbeck M
- Abstract
This paper describes the preclinical validation of the radioligand [
11 C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (α2C R) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central α2C R. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [3 H]ORM-13070. BAY 292 bound to the same binding site as [3 H]ORM-13070 and generated a good specific binding signal, with greater selectivity for α2C R. In non-human primates in vivo , [11 C]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the α2C R. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC50 for BAY 292 is 33.39 ± 11.91 ng/mL. This study aimed to demonstrate the suitability of [11 C]ORM-13070 as a PET-radioligand for the study of α2C R in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DPB, IP, TP and WP are employees of Bayer AG and may own shares or share options. MD was employee of Bayer AG at the time of conducting the study and data analysis. The study was funded by Bayer AG.ALA, CCC, DRB, EAR, KRZ, LAW are full-time employees of Invicro LLC.- Published
- 2024
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12. A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial.
- Author
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Osman AM, Toson B, Naik GR, Mukherjee S, Delbeck M, Hahn M, Muller T, Weimann G, and Eckert DJ
- Subjects
- Animals, Female, Humans, Continuous Positive Airway Pressure, Polysomnography, Sleep physiology, Swine, Nasal Sprays, Sleep Apnea, Obstructive diagnosis, Sleep Apnea, Obstructive drug therapy
- Abstract
Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K
+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 µg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2 O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P = 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals. NEW & NOTEWORTHY Preclinical findings in pigs and humans indicate that blocking potassium channels in the upper airway with topical nasal application increases pharyngeal dilator muscle activity and reduces upper airway collapsibility. In this study, BAY2586116 nasal spray (potassium channel blocker) reduced sleep apnea severity in those who had physiological improvement in upper airway collapsibility. BAY2586116 lowered the next morning's blood pressure. These findings highlight the potential for this novel therapeutic approach to improve sleep apnea in certain people.- Published
- 2024
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13. Topical Potassium Channel Blockage Improves Pharyngeal Collapsibility: A Translational, Placebo-Controlled Trial.
- Author
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Osman AM, Mukherjee S, Altree TJ, Delbeck M, Gehring D, Hahn M, Lang T, Xing C, Muller T, Weimann G, and Eckert DJ
- Subjects
- Humans, Animals, Swine, Nasal Sprays, Continuous Positive Airway Pressure, Pharynx, Sleep physiology, Sleep Apnea, Obstructive drug therapy
- Abstract
Background: Potassium (K
+ ) channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and to treat OSA. However, these findings have not yet been translated to humans., Research Question: Does a novel, potent, tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK) 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans, and secondarily, what is the optimal dose and method of topical application?, Study Design and Methods: In the preclinical study, pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during administration of placebo, 0.3 μg, 3 μg, and 30 μg nasal drops of BAY2586116. In the clinical study, 12 people with OSA instrumented with polysomnography equipment, an epiglottic pressure catheter, pneumotachograph, and nasal mask to monitor sleep and breathing performed up to four detailed upper airway sleep physiology studies. Participants received BAY2586116 (160 μg) or placebo nasal spray before sleep via a double-masked, randomized, crossover design. Most participants also returned for three additional overnight visits: (1) nasal drops (160 μg), (2) half-dose nasal spray (80 μg), and (3) direct endoscopic application (160 μg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit., Results: Consistent and sustained improvements in pharyngeal collapsibility to negative pressure were found with 3 and 30 μg of BAY2586116 vs placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of approximately 2 cm H2 O vs placebo, regardless of topical application method and dose (P < .008, mixed model) in participants with OSA., Interpretation: Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiologic findings highlight the therapeutic potential to target potassium channel mechanisms to treat OSA., Trial Registry: ClinicalTrials.gov; No.: NCT04236440; URL: www., Clinicaltrials: gov., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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14. Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC.
- Author
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Becker-Pelster EM, Hahn MG, Delbeck M, Dietz L, Hüser J, Kopf J, Kraemer T, Marquardt T, Mondritzki T, Nagelschmitz J, Nikkho SM, Pires PV, Tinel H, Weimann G, Wunder F, Sandner P, Schuhmacher J, Stasch JP, and Truebel HKF
- Subjects
- Acetylcholine, Animals, Guanylate Cyclase metabolism, Guanylate Cyclase therapeutic use, Nitric Oxide metabolism, Rats, Soluble Guanylyl Cyclase metabolism, Soluble Guanylyl Cyclase therapeutic use, Swine, Swine, Miniature metabolism, Thromboxanes therapeutic use, Vasodilator Agents, Hypertension, Pulmonary
- Abstract
Background: Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential., Methods: We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592)., Results: Mosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model., Conclusion: Inhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension., (© 2022. The Author(s).)
- Published
- 2022
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15. A lower X-gate in TASK channels traps inhibitors within the vestibule.
- Author
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Rödström KEJ, Kiper AK, Zhang W, Rinné S, Pike ACW, Goldstein M, Conrad LJ, Delbeck M, Hahn MG, Meier H, Platzk M, Quigley A, Speedman D, Shrestha L, Mukhopadhyay SMM, Burgess-Brown NA, Tucker SJ, Müller T, Decher N, and Carpenter EP
- Subjects
- Anesthetics pharmacology, Animals, Crystallography, X-Ray, Electric Conductivity, Female, Humans, Ion Channel Gating drug effects, Models, Molecular, Mutation, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Oocytes drug effects, Oocytes metabolism, Patch-Clamp Techniques, Potassium Channels, Tandem Pore Domain genetics, Potassium Channels, Tandem Pore Domain metabolism, Xenopus laevis, Nerve Tissue Proteins antagonists & inhibitors, Nerve Tissue Proteins chemistry, Potassium Channels, Tandem Pore Domain antagonists & inhibitors, Potassium Channels, Tandem Pore Domain chemistry
- Abstract
TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K
2P ) channel family-are found in neurons1 , cardiomyocytes2-4 and vascular smooth muscle cells5 , where they are involved in the regulation of heart rate6 , pulmonary artery tone5,7 , sleep/wake cycles8 and responses to volatile anaesthetics8-11 . K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli12-15 . Unlike other K2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation16 . In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below; however, the K2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an 'X-gate'-created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues (243 VLRFMT248 ) that are essential for responses to volatile anaesthetics10 , neurotransmitters13 and G-protein-coupled receptors13 . Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders.- Published
- 2020
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16. Vascular Protection and Decongestion Without Renin-Angiotensin-Aldosterone System Stimulation Mediated by a Novel Dual-Acting Vasopressin V1a/V2 Receptor Antagonist.
- Author
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Kolkhof P, Pook E, Pavkovic M, Kretschmer A, Buchmüller A, Tinel H, Delbeck M, Mondritzki T, Wasnaire P, Dinh W, Truebel H, Hüser J, and Schmeck C
- Subjects
- Animals, Aorta drug effects, Aorta metabolism, Arterial Pressure drug effects, CHO Cells, Cricetulus, Diuresis drug effects, Fibrosis, Furosemide pharmacology, Heart Failure metabolism, Heart Failure pathology, Heart Failure physiopathology, Humans, Male, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Osteopontin metabolism, Plasminogen Activator Inhibitor 1 metabolism, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors pharmacology, Rats, Rats, Wistar, Receptors, Vasopressin genetics, Receptors, Vasopressin metabolism, Signal Transduction, Vasodilation drug effects, Vasodilator Agents pharmacology, Antidiuretic Hormone Receptor Antagonists pharmacology, Heart Failure drug therapy, Receptors, Vasopressin drug effects
- Abstract
Increased plasma vasopressin levels have been shown to be associated with the progression of congestive heart failure. Vasopressin mediates water retention by renal tubular V2 receptor activation as well as vasoconstriction, cardiac hypertrophy, and fibrosis through V1a receptor activation. Therefore, we developed a novel, dual-acting vasopressin receptor antagonist, BAY 1753011, with almost identical Ki-values of 0.5 nM at the human V1a receptor and 0.6 nM at the human V2 receptor as determined in radioactive binding assays. Renal V2 antagonism by BAY 1753011 was compared with the loop diuretic furosemide in acute diuresis experiments in conscious rats. Similar diuretic efficacy was found with 300-mg/kg furosemide (maximal diuretic response) and 0.1-mg/kg BAY 1753011. Furosemide dose-dependently induced plasma renin and angiotensin I levels, while an equiefficient diuretic BAY 1753011 dose did not activate the renin-angiotensin system. BAY 1753011 dose-dependently decreased the vasopressin-induced expression of the profibrotic/hypertrophic marker plasminogen activator inhibitor-1 and osteopontin in rat cardiomyocytes, while the selective V2 antagonist satavaptan was without any effect. The combined vascular V1a-mediated and renal V2-mediated properties as well as the antihypertrophic/antifibrotic activity enable BAY 1753011 to become a viable treatment option for oral chronic treatment of congestive heart failure.
- Published
- 2019
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17. Novel non-xanthine antagonist of the A 2B adenosine receptor: From HTS hit to lead structure.
- Author
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Härter M, Kalthof B, Delbeck M, Lustig K, Gerisch M, Schulz S, Kast R, Meibom D, and Lindner N
- Subjects
- Adenosine metabolism, Animals, Pulmonary Fibrosis drug therapy, Signal Transduction, Structure-Activity Relationship, Uracil analogs & derivatives, Adenosine A2 Receptor Antagonists chemistry, High-Throughput Screening Assays, Receptor, Adenosine A2B drug effects
- Abstract
The A
2B adenosine receptor is a G protein-coupled receptor that belongs to the four member family of adenosine receptors: A1 , A2A , A2B , A3 . While adenosine-mediated A2B receptor signaling attenuates acute inflammation, facilitates tissue adaptation to hypoxia, and induces increased ischemia tolerance under conditions of an acute insult, persistently elevated adenosine levels and A2B receptor signaling are characteristics of a number of chronic disease states. In this report we describe the discovery of certain thienouracils (thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones) as antagonists of the A2B adenosine receptor by high-throughput screening from our corporate substance collection. The structure optimization of the initial screening hits led to BAY-545, an A2B receptor antagonist that was suitable for in vivo testing. The structure optimization work, SAR that was derived from there, as well as the properties of BAY-545 are also described. In vivo efficacy of BAY-545 was demonstrated in two models of lung fibrosis and data is presented., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
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18. Potent and Selective Human Neutrophil Elastase Inhibitors with Novel Equatorial Ring Topology: in vivo Efficacy of the Polar Pyrimidopyridazine BAY-8040 in a Pulmonary Arterial Hypertension Rat Model.
- Author
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von Nussbaum F, Li VM, Meibom D, Anlauf S, Bechem M, Delbeck M, Gerisch M, Harrenga A, Karthaus D, Lang D, Lustig K, Mittendorf J, Schäfer M, Schäfer S, and Schamberger J
- Subjects
- Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Humans, Hypertension, Pulmonary metabolism, Leukocyte Elastase metabolism, Models, Molecular, Molecular Structure, Proteinase Inhibitory Proteins, Secretory chemical synthesis, Pyridazines chemical synthesis, Pyrimidines chemical synthesis, Rats, Structure-Activity Relationship, Hypertension, Pulmonary drug therapy, Leukocyte Elastase antagonists & inhibitors, Proteinase Inhibitory Proteins, Secretory chemistry, Proteinase Inhibitory Proteins, Secretory pharmacology, Pyridazines chemistry, Pyridazines pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology
- Abstract
Human neutrophil elastase (HNE) is a key driver of inflammation in many cardiopulmonary and systemic inflammatory and autoimmune conditions. Overshooting high HNE activity is the consequence of a disrupted protease-antiprotease balance. Accordingly, there has been an intensive search for potent and selective HNE inhibitors with suitable pharmacokinetics that would allowing oral administration in patients. Based on the chemical probe BAY-678 and the clinical candidate BAY 85-8501 we explored further ring topologies along the equator of the parent pyrimidinone lead series. Novel ring systems were annulated in the east, yielding imidazolo-, triazolo-, and tetrazolopyrimidines in order to ensure additional inhibitor-HNE contacts beyond the S1 and the S2 pocket of HNE. The western annulation of pyridazines led to the polar pyrimidopyridazine BAY-8040, which combines excellent potency and selectivity with a promising pharmacokinetic profile. In vivo efficacy with regard to decreasing cardiac remodeling and amelioration of cardiac function was shown in a monocrotaline-induced rat model for pulmonary arterial hypertension. This demonstrated in vivo proof of concept in animals., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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19. Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.
- Author
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von Nussbaum F, Li VM, Allerheiligen S, Anlauf S, Bärfacker L, Bechem M, Delbeck M, Fitzgerald MF, Gerisch M, Gielen-Haertwig H, Haning H, Karthaus D, Lang D, Lustig K, Meibom D, Mittendorf J, Rosentreter U, Schäfer M, Schäfer S, Schamberger J, Telan LA, and Tersteegen A
- Subjects
- Dose-Response Relationship, Drug, Humans, Leukocyte Elastase metabolism, Molecular Conformation, Proteinase Inhibitory Proteins, Secretory chemistry, Pyrimidinones chemistry, Structure-Activity Relationship, Sulfones chemistry, Freezing, Leukocyte Elastase antagonists & inhibitors, Lung Diseases enzymology, Proteinase Inhibitory Proteins, Secretory pharmacology, Pyrimidinones pharmacology, Sulfones pharmacology
- Abstract
Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases., (© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.)
- Published
- 2015
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20. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
- Author
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Kolkhof P, Delbeck M, Kretschmer A, Steinke W, Hartmann E, Bärfacker L, Eitner F, Albrecht-Küpper B, and Schäfer S
- Subjects
- Animals, Autoradiography, Cardiomegaly prevention & control, Disease Models, Animal, Eplerenone, Male, Mineralocorticoid Receptor Antagonists pharmacokinetics, Naphthyridines pharmacokinetics, Natriuretic Peptide, Brain blood, Peptide Fragments blood, Rats, Rats, Sprague-Dawley, Rats, Wistar, Spironolactone pharmacokinetics, Spironolactone pharmacology, Tissue Distribution, Heart Failure prevention & control, Kidney Diseases prevention & control, Mineralocorticoid Receptor Antagonists pharmacology, Naphthyridines pharmacology, Spironolactone analogs & derivatives
- Abstract
Pharmacological blockade of the mineralocorticoid receptor (MR) ameliorates end-organ damage in chronic heart failure. However, the clinical use of available steroidal MR antagonists is restricted because of concomitant hyperkalemia especially in patients with diminished kidney function. We have recently identified a novel nonsteroidal MR antagonist, finerenone, which uniquely combines potency and selectivity toward MR. Here, we investigated the tissue distribution and chronic cardiorenal end-organ protection of finerenone in comparison to the steroidal MR antagonist, eplerenone, in 2 different preclinical rat disease models. Quantitative whole-body autoradiography revealed that [C]-labeled finerenone equally distributes into rat cardiac and renal tissues. Finerenone treatment prevented deoxycorticosterone acetate-/salt-challenged rats from functional as well as structural heart and kidney damage at dosages not reducing systemic blood pressure. Finerenone reduced cardiac hypertrophy, plasma prohormone of brain natriuretic peptide, and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses. In rats that developed chronic heart failure after coronary artery ligation, finerenone (1 mg·kg·d), but not eplerenone (100 mg·kg·d) improved systolic and diastolic left ventricular function and reduced plasma prohormone of brain natriuretic peptide levels. We conclude that finerenone may offer end-organ protection with a reduced risk of electrolyte disturbances.
- Published
- 2014
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21. A role for coagulation factor Xa in experimental pulmonary arterial hypertension.
- Author
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Delbeck M, Nickel KF, Perzborn E, Ellinghaus P, Strassburger J, Kast R, Laux V, Schäfer S, Schermuly RT, and von Degenfeld G
- Subjects
- Animals, Blood Coagulation, Enoxaparin pharmacology, Factor Xa Inhibitors, Familial Primary Pulmonary Hypertension, Hemodynamics drug effects, Hypertension, Pulmonary chemically induced, Hypertension, Pulmonary drug therapy, Hypertrophy, Right Ventricular prevention & control, Male, Monocrotaline, Morpholines pharmacology, Rats, Rats, Sprague-Dawley, Rats, Wistar, Rivaroxaban, Thiophenes pharmacology, Thrombosis etiology, Warfarin pharmacology, Factor Xa physiology, Hypertension, Pulmonary etiology
- Abstract
Aims: Anticoagulation with warfarin is recommended for the treatment of patients with pulmonary arterial hypertension (PAH). However, the therapeutic benefit of anticoagulation has not yet been demonstrated experimentally or clinically. Here, rivaroxaban, an oral, direct factor Xa (FXa) inhibitor, was compared with warfarin and enoxaparin in the prevention of right ventricular (RV) dysfunction and hypertrophy in the monocrotaline (MCT) model of pulmonary hypertension., Methods and Results: Sprague-Dawley rats (n = 10 per group) were randomized to receive rivaroxaban, warfarin, enoxaparin, or placebo before receiving a subcutaneous injection of MCT 60 mg/kg or saline. Rivaroxaban and enoxaparin were administered for 28 days starting 4 h before MCT injection; warfarin was given for 35 days initiated 7 days before MCT injection. RV haemodynamics and hypertrophy were assessed 28 days after MCT administration. Rivaroxaban dose-dependently reduced systolic and end-diastolic RV pressure increase and RV hypertrophy. Warfarin reduced RV pressure increase only. Enoxaparin had no effect on either parameter. Severe bleeding occurred in four and five rats treated with warfarin and enoxaparin, respectively, whereas no overt bleeding was observed in rats treated with rivaroxaban., Conclusion: Selective, direct inhibition of FXa by rivaroxaban effectively prevented RV dysfunction and hypertrophy in MCT-injected rats, indicating a role for coagulation factors in experimental pulmonary hypertension. Clinical investigation of the impact of early and continued administration of a specific FXa inhibitor such as rivaroxaban on the course of PAH should be considered.
- Published
- 2011
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22. Impaired left-ventricular cardiac function in male GPR30-deficient mice.
- Author
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Delbeck M, Golz S, Vonk R, Janssen W, Hucho T, Isensee J, Schäfer S, and Otto C
- Subjects
- Animals, Female, Heart Failure genetics, Heart Ventricles pathology, Male, Mice, Mice, Inbred C57BL, Receptors, Estrogen, Sex Factors, Gene Deletion, Heart Ventricles physiopathology, Receptors, G-Protein-Coupled genetics, Ventricular Function, Left
- Abstract
G-protein-coupled receptor 30 (GPR30) has been reported to act as a membrane-bound estrogen receptor that is involved in the mediation of non-genomic estradiol signalling. In this study, we demonstrated that male, but not female, GPR30-deficient mice suffer from impaired left‑ventricular cardiac function. Left ventricles from male mutant mice were enlarged. There were no malformations in the valves or outflow tract of the heart. Both the contractility and relaxation capacity of the left ventricle were reduced, leading to increased left‑ventricular end-diastolic pressure in GPR30-deficient mice. In conclusion, our data support a role for GPR30 in the gender-specific aspects of heart failure.
- Published
- 2011
- Full Text
- View/download PDF
23. A critical review of fundamental controversies in the field of GPR30 research.
- Author
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Langer G, Bader B, Meoli L, Isensee J, Delbeck M, Noppinger PR, and Otto C
- Subjects
- Animals, Estradiol pharmacology, Humans, Receptors, Estrogen, Signal Transduction drug effects, Receptors, G-Protein-Coupled metabolism, Receptors, G-Protein-Coupled ultrastructure
- Abstract
The female sex hormone estradiol plays an important role in reproduction, mammary gland development, bone turnover, metabolism, and cardiovascular function. The effects of estradiol are mediated by two classical nuclear receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). In 2005, G-protein-coupled receptor 30 (GPR30) was claimed to act as a non-classical estrogen receptor that was also activated by the ERalpha and ERbeta antagonists tamoxifen and fulvestrant (ICI 182780). Despite many conflicting results regarding the potential role of GPR30 as an estrogen receptor, the official nomenclature was changed to GPER (G-protein-coupled estrogen receptor). This review revisits the inconsistencies that still exist in the literature and focuses on selected publications that basically address the following two questions: what is the evidence for and against the hypothesis that GPR30 acts as an estrogen receptor? What is the potential in vivo role of GPR30? Thus, in the first part we focus on conflicting results from in vitro studies analysing the subcellular localization of GPR30, its ability to bind (or not to bind) estradiol and to signal (or not to signal) in response to estradiol. In the second part, we discuss the strengths and limitations of four available GPR30 mouse models. We elucidate the potential impact of different targeting strategies on phenotypic diversity., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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