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  • 1
    Language: English
    In: PloS one, 2011-03-28, Vol.6 (3), p.e18048-e18048
    Description: The release of the neurotransmitter norepinephrine (NE) is modulated by presynaptic adenosine receptors. In the present study we investigated the effect of a partial activation of this feedback mechanism. We hypothesized that partial agonism would have differential effects on NE release in isolated hearts as well as on heart rate in vivo depending on the genetic background and baseline sympathetic activity. In isolated perfused hearts of Wistar and Spontaneously Hypertensive Rats (SHR), NE release was induced by electrical stimulation under control conditions (S1), and with capadenoson 6 · 10(-8) M (30 µg/l), 6 · 10(-7) M (300 µg/l) or 2-chloro-N(6)-cyclopentyladenosine (CCPA) 10(-6) M (S2). Under control conditions (S1), NE release was significantly higher in SHR hearts compared to Wistar (766+/-87 pmol/g vs. 173+/-18 pmol/g, p〈0.01). Capadenoson led to a concentration-dependent decrease of the stimulation-induced NE release in SHR (S2/S1  =  0.90 ± 0.08 with capadenoson 6 · 10(-8) M, 0.54 ± 0.02 with 6 · 10(-7) M), but not in Wistar hearts (S2/S1  =  1.05 ± 0.12 with 6 · 10(-8) M, 1.03 ± 0.09 with 6 · 10(-7) M). CCPA reduced NE release to a similar degree in hearts from both strains. In vivo capadenoson did not alter resting heart rate in Wistar rats or SHR. Restraint stress induced a significantly greater increase of heart rate in SHR than in Wistar rats. Capadenoson blunted this stress-induced tachycardia by 45% in SHR, but not in Wistar rats. Using a [(35)S]GTPγS assay we demonstrated that capadenoson is a partial agonist compared to the full agonist CCPA (74+/-2% A(1)-receptor stimulation). These results suggest that partial adenosine A(1)-agonism dampens stress-induced tachycardia selectively in rats susceptible to strong increases in sympathetic activity, most likely due to a presynaptic attenuation of NE release.
    Subject(s): Adenosine ; Adenosine A1 Receptor Agonists - pharmacology ; Angina pectoris ; Animals ; Attenuation ; Blood Pressure - drug effects ; Cardiomyocytes ; Cardiovascular system ; Electrical stimuli ; Experiments ; Female ; Gene expression ; Heart attacks ; Heart failure ; Heart rate ; Heart Rate - drug effects ; Hypertension ; In Vitro Techniques ; Laboratory animals ; Medicine ; Nervous system ; Norepinephrine ; Norepinephrine - secretion ; Rats ; Rats, Inbred SHR ; Rats, Wistar ; Receptor, Adenosine A1 - metabolism ; Receptors ; Restraint, Physical ; Rodents ; Stimulation ; Stress ; Stress, Physiological - drug effects ; Stresses ; Tachycardia
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: British journal of pharmacology, 1997-02, Vol.120 (4), p.681-689
    Description: 1 We studied the effects of 3‐(5′‐hydroxymethyl‐2′furyl)‐1‐benzyl indazole (YC‐1) on the activity of purified soluble guanylyl cyclase (sGC), the formation of guanosine‐3′: 5′cyclic monophosphate (cyclic GMP) in vascular smooth muscle cells (VSMC), and on the tone of rabbit isolated aortic rings preconstricted by phenylephrine (PE). In addition, we assessed the combined effect of YC‐1, and either NO donors, or superoxide anions on these parameters. 2 YC‐1 elicited a direct concentration‐dependent activation of sGC (EC50 18.6 ± 2.0 μm), which was rapid in onset and quickly reversible upon dilution. YC‐1 altered the enzyme kinetics with respect to GTP by decreasing Km and increasing Vmax. Activation of sGC by a combination of sodium nitroprusside (SNP) and YC‐1 was superadditive at low and less than additive at high concentrations, indicating a synergistic activation of the enzyme by both agents. A specific inhibitor of sGC, 1H‐(1,2,4)‐oxdiazolo‐(4,3‐a)‐6‐bromo‐quinoxazin‐l‐one (NS 2028), abolished activation of the enzyme by either compound. 3 YC‐1 induced a concentration‐dependent increase in intracellular cyclic GMP levels in rat cultured aortic VSMC, which was completely inhibited by NS 2028. YC‐1 applied at the same concentration as SNP elicited 2.5 fold higher cyclic GMP formation. Cyclic GMP‐increases in response to SNP and YC‐1 were additive. 4 YC‐1 relaxed preconstricted endothelium‐denuded rabbit aortic rings in a concentration‐dependent manner (50% at 20 μM) and markedly increased cyclic GMP levels. Relaxations were inhibited by NS 2028. A concentration of YC‐1 (3 μm), which elicited only minor effects on relaxation and cyclic GMP, increased the vasodilator potency of SNP and nitroglycerin (NTG) by 10 fold and markedly enhanced SNP‐and NTG‐induced cyclic GMP formation. 5 Basal and YC‐1‐stimulated sGC activity was sensitive to inhibition by superoxide (O2−) generated by xanthine/xanthine oxidase, and was protected from this inhibition by superoxide dismutase (SOD). YC‐1‐stimulated sGC was also sensitive to inhibition by endogenously generated (O2− in rat preconstricted endothelium‐denuded aortic rings. Relaxation to YC‐1 was significantly attenuated in aortae from spontaneously hypertensive rats (SHR), which generated O2− at a higher rate than aortae from normotensive Wistar Kyoto rats (WKY). SOD restored the vasodilator responsiveness of SHR rings to YC‐1. 6 In conclusion, these results indicate that YC‐1 is an NO‐independent, O2−‐sensitive, direct activator of sGC in VSMC and exerts vasorelaxation by increasing intracellular cyclic GMP levels. The additive or even synergistic responses to NO‐donors and YC‐1 in cultured VSMC and isolated aortic rings apparently reflect the direct synergistic action of YC‐1 and NO on the sGC. The synergism revealed in this in vitro study suggests that low doses of YC‐1 may be of therapeutic value by permitting the reduction of nitrovasodilator dosage.
    Subject(s): Animals ; Antianginal agents. Coronary vasodilator agents ; Biological and medical sciences ; Cardiovascular system ; Cells, Cultured ; Cyclic GMP - biosynthesis ; Enzyme Activation - drug effects ; Guanylate Cyclase - metabolism ; In Vitro Techniques ; Indazoles - pharmacology ; Male ; Medical sciences ; Muscle Relaxation - drug effects ; Muscle, Smooth, Vascular - drug effects ; nitric oxide ; Nitric Oxide - analysis ; NS 2028 (1H‐(1,2,4)‐oxdiazolo‐(4,3‐a)‐6‐bromo‐quinoxazin‐1‐one) ; oxygen radicals ; Papers ; Pharmacology. Drug treatments ; Rabbits ; Rats ; Rats, Inbred WKY ; relaxation ; soluble guanylyl cyclase ; soluble guanylyl cyclase vascular smooth muscle ; Superoxides - pharmacology ; vascular smooth muscle ; Vasodilator Agents - pharmacology ; YC‐1 (3‐(5′‐hydroxymethyl‐2′furyl)‐1‐benzyl indazole)
    ISSN: 0007-1188
    E-ISSN: 1476-5381
    Source: Academic Search Ultimate
    Source: Wiley Online Library All Journals
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 3
    Language: English
    In: Journal of medicinal chemistry, 2020-10-22, Vol.63 (20), p.11639-11662
    Description: Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well-tolerated antifibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expressed in the lung tissue and constitutes an attractive target for the treatment of fibrotic lung diseases. Herein, we present our research toward novel quinoline-based hFP-R antagonists, including synthesis and detailed structure–activity relationship (SAR). Starting from a high-throughput screening (HTS) hit of our corporate compound library, multiple parameter improvementsincluding increase of the relative oral bioavailability F rel from 3 to ≥100%led to a highly potent and selective hFP-R antagonist with complete oral absorption from suspension. BAY-6672 (46) representsto the best of our knowledgethe first reported FP-R antagonist to demonstrate in vivo efficacy in a preclinical animal model of lung fibrosis, thus paving the way for a new treatment option in IPF.
    Subject(s): Administration, Oral ; Animals ; Disease Models, Animal ; Humans ; Idiopathic Pulmonary Fibrosis - drug therapy ; Idiopathic Pulmonary Fibrosis - metabolism ; Lung - drug effects ; Lung - metabolism ; Lung - pathology ; Male ; Mice ; Molecular Structure ; Quinolines - chemical synthesis ; Quinolines - chemistry ; Quinolines - therapeutic use ; Rats ; Rats, Wistar ; Receptors, Prostaglandin - antagonists & inhibitors ; Structure-Activity Relationship
    ISSN: 0022-2623
    E-ISSN: 1520-4804
    Source: Hellenic Academic Libraries Link
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  • 4
    Language: English
    In: ChemMedChem, 2017-05-22, Vol.12 (10), p.728-737
    Description: Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosine A1 receptors (A1Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation. These unwanted effects can be overcome by using partial A1R agonists. Starting from previously reported capadenoson we evaluated options to tailor A1R agonists to a specific partiality range, thereby optimizing the therapeutic window. This led to the identification of the potent and selective agonist neladenoson, which shows the desired partial response on the A1R, resulting in cardioprotection without sedative effects or cardiac AV blocks. To circumvent solubility and formulation issues for neladenoson, a prodrug approach was pursued. The dipeptide ester neladenoson bialanate hydrochloride showed significantly improved solubility and exposure after oral administration. Neladenoson bialanate hydrochloride is currently being evaluated in clinical trials for the treatment of heart failure. Good gets even better: Partial adenosine A1 receptor (A1R) activation is associated with a positive impact on heart failure without the detriments of full A1R agonism. Starting from capadenoson, we describe the identification of neladenoson bialanate hydrochloride, which has a good pharmacokinetic and safety profile. Neladenoson bialanate hydrochloride is currently being assessed in clinical studies for the treatment of heart failure.
    Subject(s): Adenosine ; adenosine A1 receptor ; Arrhythmia ; biological activity ; dicyanopyridines ; Drug therapy ; Heart failure ; medicinal chemistry ; partial agonists ; Physiological aspects ; prodrugs
    ISSN: 1860-7179
    E-ISSN: 1860-7187
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Cardiovascular research, 2009-04-01, Vol.82 (1), p.30-39
    Description: Aims Inhibition of phosphodiesterase 5 (PDE5) decreases pulmonary pressure and improves symptoms in patients with pulmonary arterial hypertension. It is unclear however, whether inhibition of PDE5 can prevent myocardial remodelling during right-ventricular pressure overload. Methods and results Right-ventricular pressure overload was produced in male rats in a pulmonary hypertension model (monocrotaline 60 mg/kg s.c.) or by surgical pulmonary artery banding. PDE5 inhibition using oral sildenafil (50 mg/kg/day in drinking water) or placebo was initiated 14 days after monocrotaline treatment and continued for 14 days until final examination. In the pulmonary artery banding groups, rats were treated with sildenafil (50 mg/kg/day) or placebo for 21 days following surgical pulmonary artery banding. At the final experiments, right-ventricular haemodynamics were measured and remodelling was analysed using histological, biochemical, and gene expression markers. Both monocrotaline and pulmonary artery banding increased right-ventricular systolic pressure to ∼80 mmHg. In parallel, both interventions induced markers of hypertrophy (upregulation of natriuretic peptides, increase in myocyte diameter) and fibrosis (upregulation of collagen types 1A2 and 3A1) as well as mRNA expression of the tissue inhibitor of matrix metalloproteases 1 and osteopontin in the right ventricle. In monocrotaline model, sildenafil decreased pulmonary pressure, reduced right-ventricular hypertrophy, and prevented fibrosis marker gene upregulation. After pulmonary artery banding, in contrast, sildenafil increased markers of myocardial remodelling and right-ventricular myocyte diameter. Conclusion Sildenafil prevents myocardial remodelling in pulmonary hypertension through an indirect action via right-ventricular unloading.
    Subject(s): Administration, Oral ; Animals ; Biological and medical sciences ; Blood Pressure - drug effects ; Cardiology. Vascular system ; Cyclic GMP - blood ; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism ; Disease Models, Animal ; Fibrillar Collagens - metabolism ; Fibrosis ; Hemodynamics - drug effects ; Hypertension, Pulmonary - chemically induced ; Hypertension, Pulmonary - drug therapy ; Hypertension, Pulmonary - enzymology ; Hypertension, Pulmonary - physiopathology ; Hypertrophy, Right Ventricular - enzymology ; Hypertrophy, Right Ventricular - etiology ; Hypertrophy, Right Ventricular - physiopathology ; Hypertrophy, Right Ventricular - prevention & control ; Male ; Medical sciences ; Monocrotaline ; Myocardium - enzymology ; Myocardium - pathology ; Natriuretic Peptides - metabolism ; Osteopontin - metabolism ; Phosphodiesterase 5 Inhibitors ; Phosphodiesterase Inhibitors - administration & dosage ; Phosphodiesterase Inhibitors - pharmacokinetics ; Phosphodiesterase Inhibitors - pharmacology ; Piperazines - administration & dosage ; Piperazines - pharmacokinetics ; Piperazines - pharmacology ; Pneumology ; Pulmonary Artery - surgery ; Pulmonary hypertension ; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases ; Purines - administration & dosage ; Purines - pharmacokinetics ; Purines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Remodelling ; RNA, Messenger - metabolism ; Sildenafil ; Sildenafil Citrate ; Stroke Volume - drug effects ; Sulfones - administration & dosage ; Sulfones - pharmacokinetics ; Sulfones - pharmacology ; Time Factors ; Tissue Inhibitor of Metalloproteinase-1 - metabolism ; Ventricular Pressure - drug effects ; Ventricular Remodeling - drug effects
    ISSN: 0008-6363
    E-ISSN: 1755-3245
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: Cardiovascular research, 2011-10-01, Vol.92 (1), p.159-168
    Description: 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.
    Subject(s): Animals ; Biological and medical sciences ; Blood Coagulation ; Cardiology. Vascular system ; Enoxaparin - pharmacology ; Factor Xa - physiology ; Factor Xa Inhibitors ; Familial Primary Pulmonary Hypertension ; Hemodynamics - drug effects ; Hypertension, Pulmonary - chemically induced ; Hypertension, Pulmonary - drug therapy ; Hypertension, Pulmonary - etiology ; Hypertrophy, Right Ventricular - prevention & control ; Male ; Medical sciences ; Monocrotaline ; Morpholines - pharmacology ; Pneumology ; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Rivaroxaban ; Thiophenes - pharmacology ; Thrombosis - etiology ; Warfarin - pharmacology
    ISSN: 0008-6363
    E-ISSN: 1755-3245
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: ChemMedChem, 2017-05-22, Vol.12 (10), p.728-737
    ISSN: 1860-7179
    E-ISSN: 1860-7187
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 8
    Language: English
    In: ChemMedChem, 2017-05-01, Vol.12 (10), p.728
    Description: Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosineA1 receptors (A1Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation. These unwanted effects can be overcome by using partial A1R agonists. Starting from previously reported capadenoson we evaluated options to tailor A1R agonists to a specific partiality range, thereby optimizing the therapeutic window. This led to the identification of the potent and selective agonist neladenoson, which shows the desired partial response on the A1R, resulting in cardioprotection without sedative effects or cardiac AV blocks. To circumvent solubility and formulation issues for neladenoson, a prodrug approach was pursued. The dipeptide ester neladenoson bialanate hydrochloride showed significantly improved solubility and exposure after oral administration. Neladenoson bialanate hydrochloride is currently being evaluated in clinical trials for the treatment of heart failure.
    Subject(s): Adenosine ; Bradycardia ; Cardiovascular diseases ; Clinical trials ; Coronary artery disease ; Heart ; Heart diseases ; Ischemia ; Medical research ; Oral administration ; Pharmacology ; Receptors ; Regeneration ; Reperfusion ; Solubility ; Tissues
    ISSN: 1860-7179
    E-ISSN: 1860-7187
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: Bioorganic & medicinal chemistry letters, 2010, Vol.20 (19), p.5891-5894
    Description: Potent and selective adenosine A 1 receptor antagonists were disclosed. SAR and pharmacological profile of selected compounds were discussed.
    Subject(s): 5-Aminopyrazole ; Adenosin A 1 receptor antagonist ; Adenosine A1 Receptor Antagonists - chemical synthesis ; Adenosine A1 Receptor Antagonists - chemistry ; Adenosine A1 Receptor Antagonists - pharmacokinetics ; Animals ; Biological and medical sciences ; Cardiovascular system ; Diuresis ; Heart failure ; Medical sciences ; Miscellaneous ; Natriuresis ; Pharmacology. Drug treatments ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacokinetics ; Rats ; Rats, Wistar ; Receptor, Adenosine A1 - chemistry ; Receptor, Adenosine A1 - metabolism ; Structure-Activity Relationship ; Urinary system
    ISSN: 0960-894X
    E-ISSN: 1464-3405
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
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  • 10
    Language: English
    In: PloS one, 2011-03-28, Vol.6 (3), p.e18048
    Description: The release of the neurotransmitter norepinephrine (NE) is modulated by presynaptic adenosine receptors. In the present study we investigated the effect of a partial activation of this feedback mechanism. We hypothesized that partial agonism would have differential effects on NE release in isolated hearts as well as on heart rate in vivo depending on the genetic background and baseline sympathetic activity. In isolated perfused hearts of Wistar and Spontaneously Hypertensive Rats (SHR), NE release was induced by electrical stimulation under control conditions (S1), and with capadenoson 6 #183; 10.sup.-8 M (30 [micro]g/l), 6 #183; 10.sup.-7 M (300 [micro]g/l) or 2-chloro-N.sup.6 -cyclopentyladenosine (CCPA) 10.sup.-6 M (S2). Under control conditions (S1), NE release was significantly higher in SHR hearts compared to Wistar (766+/-87 pmol/g vs. 173+/-18 pmol/g, p0.01). Capadenoson led to a concentration-dependent decrease of the stimulation-induced NE release in SHR (S2/S1 = 0.90#177;0.08 with capadenoson 6 #183; 10.sup.-8 M, 0.54#177;0.02 with 6 #183; 10.sup.-7 M), but not in Wistar hearts (S2/S1 = 1.05#177;0.12 with 6 #183; 10.sup.-8 M, 1.03#177;0.09 with 6 #183; 10.sup.-7 M). CCPA reduced NE release to a similar degree in hearts from both strains. In vivo capadenoson did not alter resting heart rate in Wistar rats or SHR. Restraint stress induced a significantly greater increase of heart rate in SHR than in Wistar rats. Capadenoson blunted this stress-induced tachycardia by 45% in SHR, but not in Wistar rats. Using a [.sup.35 S]GTP[gamma]S assay we demonstrated that capadenoson is a partial agonist compared to the full agonist CCPA (74+/-2% A.sub.1 -receptor stimulation). These results suggest that partial adenosine A.sub.1 -agonism dampens stress-induced tachycardia selectively in rats susceptible to strong increases in sympathetic activity, most likely due to a presynaptic attenuation of NE release.
    Subject(s): Adenosine ; Heart beat ; Hypertension ; Noradrenaline ; Stress management
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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