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WO1993012068A1 - S-nitrosothiols utilises comme decontracturants des muscles lisses et leurs utilisations therapeutiques - Google Patents

S-nitrosothiols utilises comme decontracturants des muscles lisses et leurs utilisations therapeutiques Download PDF

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Publication number
WO1993012068A1
WO1993012068A1 PCT/US1992/010447 US9210447W WO9312068A1 WO 1993012068 A1 WO1993012068 A1 WO 1993012068A1 US 9210447 W US9210447 W US 9210447W WO 9312068 A1 WO9312068 A1 WO 9312068A1
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nitroso
compound
equals
nitrosothiol
formula
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PCT/US1992/010447
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English (en)
Inventor
Jonathan Stamler
Joseph Loscalzo
Adam Slivka
Daniel Simon
Robert Brown
Jeffrey Drazen
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Brigham And Women's Hospital
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Priority claimed from US07/943,834 external-priority patent/US5380758A/en
Application filed by Brigham And Women's Hospital filed Critical Brigham And Women's Hospital
Publication of WO1993012068A1 publication Critical patent/WO1993012068A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to the use of low molecular weight S- nitrosothiols, such as S-nitroso-N-acetylcysteine, S-nitroso-glutathione, S- nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-penicillamine and S-nitroso- captopril, to relax non- vascular smooth muscle.
  • S- nitrosothiols such as S-nitroso-N-acetylcysteine, S-nitroso-glutathione, S- nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-penicillamine and S-nitroso- captopril
  • S- nitrosothiols such as S-nitroso-N-acetylcysteine, S-nitroso-glutathione, S- nitroso-homocysteine,
  • the invention also relates to the use of S-nitrosothiols for the treatment or prevention of disorders which involve non-vascular smooth muscle, such as respiratory disorders, gastrointestinal disorders, urological dysfunction, impotence, uterine dysfunction or premature labor.
  • the invention also relates to the use of S-nitrosothiols to ameliorate smooth muscle contraction or spasm and thus, facilitate diagnostic or therapeutic procedures, such as bronchoscopy, endoscopy, laparoscopy, and cystoscopy.
  • S-nitrosothiols may also be used to increase hemoglobin-oxygen binding, and thus enhance oxygen transport to bodily tissues.
  • endothelium-derived relaxing factor a vascular relaxing factor, known as endothelium-derived relaxing factor (EDRF), which has been identified as nitric oxide (NO), or a closely related derivative thereof.
  • EDRF endothelium-derived relaxing factor
  • NO nitric oxide
  • NO nitric oxide
  • S-nitrosothiols are adducts that form readily under physiologic conditions from the reaction of NO with reduced low molecular weight thiols (Oae et al., Org. Prep. Proc. Int. 15(3): 165-198 (1983)). These compounds have half-lives that are significantly greater than that of NO and, like EDRF, possess vasorelaxant activity that is mediated through activation of guanylate cyclase (Kowaluk et al., J. Pharmacol. Exp. Ther. 256:1256-
  • Pulmonary immune responses result in the liberation of cytokines and inflammatory mediators which contribute to the narrowing of airway smooth muscle.
  • pulmonary endothelial cells, macrophages and polymorphonuclear leukocytes are believed to induce nitric oxide synthetase, thus serving as a source of NO.
  • NO production in the lung are not known.
  • the potential beneficial effects of NO through bronchodilation may be counterbalanced by generation of toxic nitrogen oxides that form readily under the high ambient concentration of oxygen and other reactive oxygen species.
  • NO ⁇ reacts with the redox metal site on hemoglobin to form methemoglobin, which inhibits oxygen-hemoglobin binding, thereby significantly reducing the oxygen-carrying capacity of the blood.
  • Non-vascular smooth muscle is present in numerous organ systems throughout the body, and has a vital role in the physiological function of these systems.
  • airway smooth muscle plays a critical role in constriction and dilation of bronchi.
  • the sphincter of Oddi a smooth muscle connection between the bile duct and duodenum, provides tonic contraction which serves to prevent reflux of duodenal contents into the pancreatic and bile ducts, and promotes filling of the gall bladder.
  • esophageal (sphincters and body) intestinal and colonic motility is regulated by smooth muscle. Smooth muscle of the bladder body, bladder base, and proximal urethra plays an important role in urological function, and erectile function is mediated by relaxation of corpus cavernosal smooth muscle.
  • non-vascular smooth muscle are very important in numerous physiological systems.
  • a variety of significant clinical disorders occur, which involve contraction, spasm, or failure to achieve the necessary relaxation of smooth muscle.
  • Examples of such disorders include airway obstruction (i.e., asthma, bronchitis and emphysema), bladder dysfunction, gastrointestinal muscle spasm (i.e., irritable bowel syndrome, achalasia, dumping disorders), and impotence.
  • airway obstruction i.e., asthma, bronchitis and emphysema
  • bladder dysfunction i.e., irritable bowel syndrome, achalasia, dumping disorders
  • impotence i.e., irritable bowel syndrome, achalasia, dumping disorders
  • This invention is based on the discovery by the inventors that S- nitrosothiols exert a potent relaxant effect on non-vascular smooth muscle.
  • S-nitrosothiol compounds may be used as a therapeutic modality in disorders which involve smooth muscle relaxation.
  • the invention is directed to an S-nitrosothiol compound which has the formula:
  • X 2 to 20.
  • the invention is also directed to an S-nitrosothiol compound which has the formula:
  • the invention is also directed to an S-nitrosothiol compound which has the formula:
  • X equals 2 to 20 and Y is selected from the group consisting of fluoro, C 1 -C 6 alkoxy, cyano, carboxamido, C 3 -C 6 cycloalkyl, aralkoxy, C 2 -C 6 alkylsulfinyl, arylthio, C 1 -C 6 alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbamoyl, C 1 C 6 N-alkylcarbamoyl, C 2 -C 15 N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl; wherein aryl includes benzyl, naphthyl, and anthracenyl groups.
  • the invention is also directed to the use of S-nitrosothiols for the treatment or prevention of disorders associated with relaxation of smooth muscle, such as airway obstruction, gastrointestinal spasm, bladder dysfunction and impotence.
  • the invention is also directed to the use of S-nitrosothiols to alleviate smooth muscle contraction and spasm, and thus facilitate procedures involving diagnostic instrumentation such as endoscopy and bronchoscopy.
  • this invention is directed to a method for relaxing airway smooth muscle by administering a therapeutically effective amount of an S- nitrosothiol compound to an animal.
  • the S-nitrosothiol compound may be selected from the group consisting of S-nitroso-N-acetylcysteine, S-nitroso- glutathione, S-nitroso-cysteine, S-nitroso-homocysteine, S-nitroso-penicillamine and S-nitroso-captopril.
  • the S-nitrosothiol compound may be selected from the group consisting of a compound having the formula:
  • X 2 to 20.
  • the invention is also directed to an S-nitrosothiol compound which has the formula:
  • the invention is also directed to an S-nitrosothiol compound which has the formula:
  • X equals 2 to 20 and Y is selected from the group consisting of fiuoro, C 1 -C 6 alkoxy, cyano, carboxamido, C 3 -C 6 cycloalkyl, aralkoxy, C 2 -C 6 alkylsulfinyl, arylthio, C 1 -C 6 alkylamino, C 2 -C 15 dialkylamino, hydroxy, carbomoyl, C 1 C 6 N-alkylcarbamoyl, C 2 -C 15 N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl; wherein aryl includes benzyl, naphthyl, and anthracenyl groups.
  • the invention is also directed to a method for treatment or prevention of respiratory disorders by administering a therapeutically effective amount of S-nitrosothiol compound to an animal.
  • Respiratory disorders include obstructive lung disease, emphysema, asthma, brondiitis, fibrosis, excessive mucus secretion, obstruction of air flow, and lung disorders resulting from post-surgical complications.
  • the invention is also directed to a method for relaxing gastrointestinal smooth muscle by administering a therapeutically effective amount of an S- nitrosothiol compound to an animal.
  • the invention is also directed to a method for ameliorating contraction or spasm of gastrointestinal smooth muscle associated with endoscopic procedures, by administering a therapeutically effective amount of an S- nitrosothiol compound to an animal.
  • the invention is also directed to a method for relaxing corpus cavernosum smooth muscle by administering a therapeutically effective amount of an S-nitrosothiol compound to an animal.
  • the invention is directed to a method for the treatment or prevention of impotence by administering a therapeutically effective amount of an S- nitrosothiol compound to an animal.
  • the invention is also directed to a method for relaxing bladder smooth muscle by administering a therapeutically effective amount of an S-nitrosothiol compound to an animal.
  • the invention is also directed to a method for relaxing uterine smooth muscle by administering a therapeutically effective amount of an S-nitrosothiol compound to an animal.
  • the invention is also directed to the administration of said S- nitrosothiol compounds for the methods of the invention, as part of the pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • the invention is also directed to the methods of the invention wherein the pharmaceutical composition containing the S-nitrosothiol compound is administered to an animal by a route comprising oral, sublingual, intravenous, topical, intramuscular or intranasal delivery.
  • the invention is also directed to a method for increasing the capacity of hemoglobin to bind oxygen, comprising admimstering a therapeutically effective amount of an S-nitrosothiol compound to an animal in need thereof.
  • the invention is also directed to a method for increasing oxygen transport to bodily tissues, comprising administering a therapeutically effective amount of an S-nitrosothiol compound to an animal in need thereof.
  • the invention is also directed to a method for the treatment or prevention of disorders associated with insufficient oxygen supply to bodily tissues, comprising admimstering a therapeutically effective amount of an S- nitrosothiol to an animal in need thereof.
  • FIGURE 1 Inhibition of the Sphincter of Oddi by administration of
  • FIGURE 2 Inhibition of duodenal motility by administration of S- nitroso-N-acetylcysteine.
  • FIGURE 3 Side-by-side comparison of the relaxant effect of specific S-nitrosothiols on guinea pig tracheal muscle.
  • FIGURE 4 Dose-dependent relaxant effect of specific S- nitrosothiols on guinea pig tracheal muscle contracted with 3 ⁇ M, as compared to the reactant and NO. a: S-nitroso-glutathione
  • FIGURE 5 Relaxant activities of S-nitroso-N-acetylcysteine (A) and
  • S-nitroso-captopril (B) determined against contractions induced by leukotriene D 4 , histamine and methacholine.
  • FIGURE 6 The course of relaxation induced by S-nitroso-N- acetylcysteine (5 x 10 -6 M) over 60 minutes.
  • FIGURE 7 The relaxation response to S-nitroso-glutathione in guinea pig airway (A) and rabbit aorta (B).
  • FIGURE 8 Tracheal relaxant effects of S-nitroso-N-acetylcysteine, isoproterenol, and theophylline.
  • FIGURE 9 Inhibition of tracheal relaxation to S-nitroso-N- acetylcysteine by hemoglobin and methylene blue.
  • FIGURE 10 Cyclic GMP determinations in tracheal rings incubated with 100 ⁇ M S-nitroso-N-acetylcysteine.
  • FIGURE 11 Comparison between the relaxant effect of S-nitroso- glutathione and nitrite upon human tracheal smooth muscle.
  • FIGURE 12 Comparison between the relaxant effect of S-nitroso- glutathione and glutathione upon human tracheal smooth muscle.
  • FIGURE 13 Comparison between the relaxant effect of S-nitroso-N- acetylcysteine and N-acetylcysteine upon human tracheal smooth muscle.
  • FIGURE 14 Tracheal relaxant effects of theophylline, isoproterenol,
  • FIGURE 15 Cyclic GMP response to S-nitroso-N-acetylcysteine in human airways.
  • FIGURE 16 SNOAC-induced airway relaxation is not inhibited by methylene blue.
  • FIGURE 17 S-nitrosylation of hemoglobin.
  • FIGURE 18 UV spectrum of hemoglobin incubated with S-nitroso-N- acetylcysteine.
  • FIGURE 19 Reaction of nitric oxide at the iron-binding site of hemoglobin. Description Of The Preferred Embodiments
  • the invention is based on the discovery by the inventors that S- nitrosothiols relax non-vascular smooth muscle, and possess unique and different relaxant activities, kinetic properties and membrane permeability, and thus, may be used to treat or prevent disorders which involve non-vascular smooth muscle.
  • S-nitrosothiol refers to a compound which is selected from the group consisting of S-nitroso-N-acetylcysteine, S- nitroso-glutathione, S-nitroso-cysteine, S-nitroso-homocysteine, S-nitroso- pantathoeine derivatives, S-nitroso-penicillamine and S-nitroso-captopril.
  • S-nitrosothiol refers to particular novel S-nitrosothiol compounds synthesized by the inventors, for use as smooth muscle relaxants.
  • the compounds represented by the general formula of CH 3 (CH 2 ) x SNO are long carbon-chain lipophilic nitrosothiols.
  • the compounds represented by the general formula of HS(C H 2 ) x SNO are S- nitrosodithiols, possessing an additional thiol group.
  • the compounds represented by the general formula of ONS(CH 2 ) x Y are S-nitrosothiols which possess other functional groups, in addition to the thiol.
  • the invention is related to the discovery that S-nitrosothiol compounds relax non-vascular smooth muscle.
  • these compounds may be used to treat or prevent those pathophysiologic conditions which result from, or involve, constriction of smooth muscle, or those which necessitate therapeutic intervention to achieve smooth muscle relaxation.
  • One embodiment of the invention relates to the administration of a therapeutically effective amount of an S-nitrosothiol to an animal to relax airway smooth muscle.
  • airway smooth muscle refers to the smooth muscle lining the bronchi or tracheal region.
  • S-nitrosothiols exert a potent relaxant effect upon airway smooth muscle.
  • these compounds may be administered as therapeutic agents for the treatment or prevention of respiratory disorders.
  • respiratory disorder refers to any impairment of lung function which involves constriction of airways and changes in blood gas levels or lung function.
  • airway obstruction constitutes a respiratory disorder which occurs as a result of acute pulmonary impairment or obstructive lung disease. Severe airway obstruction may ultimately result in life-threatening respiratory failure. Airway obstruction occurs in patients with chronic obstructive lung diseases, such as emphysema and bronchitis. These patients often experience recurrent episodes of respiratory failure as a result of severe airway obstruction. Emphysema can result in significant disability due to dyspnea, extreme restriction of physical activity, and mortality.
  • Airway obstruction also results from asthma, a disorder characterized by increased responsiveness of the tracheobronchial tree to various stimuli, and which leads to generalized airway constriction manifested by dyspnea, cough and wheezing. Asthma sufferers often experience acute exacerbations of bronchoconstriction, which may be life-threatening.
  • cystic fibrosis Another obstructive lung disease, cystic fibrosis, results from abnormal exocrine gland function. Clinical manifestations include excessive mucous secretion, hypertrophy of bronchial glands, infection, and inflammatory and structural changes in the airways which lead to obstruction and ventilation- perfusion imbalance.
  • Acute respiratory failure may result not only from obstructive disease, but also as a consequence of airway constriction secondary to pneumonia, thromboembolism, left ventricular failure and pneumothorax. Acute respiratory failure may also result from ventilation-perfusion imbalance.
  • bronchodilatory agents such as isoproterenol, given by inhalation or subcutaneous injection, and methylxanthines, such as theophylline, given orally or by infusion.
  • the margin of safety for theophylline administration is relatively narrow.
  • the minimum therapeutic concentration in plasma is 6 to 10 ⁇ g/ml, and unacceptable symptoms of toxicity usually appear at or above 20 ⁇ g/ml. Still higher concentrations can lead to serious central nervous system toxicity, with long-term ingestion of theophylline being a predisposing factor in such toxicity.
  • the clearance of theophylline is influenced by genetic, developmental and environmental factors to a significant degree, it is necessary to titrate the dosage cautiously against clinical observations of beneficial or toxic effects, with periodic determination of the concentration of the drug in plasma (Gilman A.G., The Pharmacological Basis af Therapeutics, Pergamon Press, New York, (1990)).
  • Isoproterenol a non-selective ⁇ -agonist, produces cardiovascular side effects such as palpitations, sinus tadiycardia and more serious arrhythmias.
  • S-nitrosothiols for the treatment of airway obstruction provides significant advantages over current methods of treatment.
  • S-nitrosothiols eliminates the untoward side effects associated with ⁇ - agonists and methylxanthines.
  • S-nitrosothiols also potently inhibit platelets and neutrophils which have been implicated in the pathogenesis of asthma.
  • cyclic GMP agonists act synergistically with cyclic AMP agonists to provide bronchodilation, not obtainable by individual agents.
  • S-nitrosothiols also cause relaxation of smooth muscle by a cGMP-independent mechanism.
  • Another mechanism by which bronchodilation is effected provides an opportunity for combination therapy, because the independent mechanisms have potential for synergy.
  • S-nitrosothiols deliver NO in its most biologically relevant, and non-toxic form. This is critical, because the pharmacological efficacy of NO, particularly in airways, depends upon the form in which it is delivered.
  • S- nitrosothiols can deliver NO as charged species, nitrosonium (NO + ) or nitroxyl (NO), as opposed to the uncharged NO radical (NO ⁇ ). This is important because the charged species behave in a very different manner from NO ⁇ with respect to chemical reactivity.
  • nitrosonium and nitroxyl do not react with O 2 or O 2 species to produce toxic oxides of nitrogen, and are also resistant to decomposition in the presence of redox metals. Consequently, administration of these NO equivalents does not result in the generation of toxic by-products, or elimination of the active NO moiety.
  • S-nitrosothiols provide a means for achieving the smooth muscle relaxant effects of NO, and at the same time, alleviate significant adverse effects previously associated with NO therapy.
  • S-nitrosothiols may also be used as a means to deliver free NO in a stable and non-toxic form, for use in free NO therapy.
  • S-nitrosothiols may also be used to increase the oxygen-binding capacity of hemoglobin.
  • Hemoglobin is a globular protein, which binds reversibly to blood oxygen through passive diffusion from entry of air into the lungs. Hemoglobin-oxygen binding greatly increases the capacity of the blood to transport oxygen to bodily tissues; thus, the binding affinity between hemoglobin and oxygen is a critical factor in determining the level of oxygen transport to the tissues.
  • S-nitrosothiols do not react with the iron-binding site of hemoglobin, as does NO ⁇ , but instead, bind to the thiol group. Thus, methemoglobin formation is prevented and hemoglobin-oxygen binding is unimpaired.
  • S-nitrosothiols not only prevent impairment, of binding, but actually increase hemoglobin- oxygen binding. Therefore, S-nitrosothiols may be used to increase the oxygen-carrying capacity of the blood, and oxygen transport to bodily tissues. As a result, these compounds may be useful in the treatment of disorders which are associated with insufficient oxygen transport, or in clinical situations in which increased oxygen transport is needed. Examples of such clinical situations include, but are not limited to, hypoxic disorders resulting from pneumothorax, airway obstruction, paralysis or weakness of the respiratory muscles, inhibition of respiratory centers by drugs or other agents, or other instances of decreased pulmonary ventilation. Additional clinical indications include impaired alveolar gas diffusion such as occurs in interstitial fibrosis, bronchiole constriction, pulmonary edema, pneumonia, hemorrhage, drowning, anemias, arteriovenous shunts.
  • VIP vasoactive intestinal peptide
  • S-nitrosothiols are also suitable for direct instillation into the lungs by bronchoscopic means.
  • This topical administration permits titration of dose, eliminates the untoward side effects of systemic therapy, and enables the use of combination therapy, involving a topical S-nitrosothiol in conjunction with a systemic agent, in problematic cases.
  • This topical therapy would also facilitate endoscopy by suppressing the cough reflex and associated bronchospasm.
  • N-acetylcysteine is one such agent.
  • S-nitroso-N-acetylcysteine is advantageous because it possesses both mucolytic and bronchodilator capabilities.
  • the mucolytic activity of the compound depends upon the amount of thiol which is preserved after NO delivery.
  • S-nitrosothiol compounds which contain more than one thiol (dithiol compounds) are particularly suitable for achieving mucolysis.
  • the long-chain lipophilic S-nitrosothiols which contain more than one thiol are advantageous as mucolytic agents because they have a free thiol, and their lipophilic property facilitates penetration of the compound into the lipid portion responsible for the tenacious viscosity of mucous.
  • S- nitrosothiols may also be used to facilitate diagnostic and therapeutic bronchoscopy.
  • bronchoscopy refers to the procedure in which a flexible fiberoptic, or rigid bronehoscope is introduced into the tracheobronchial tree for the purpose of bronchial visualization, lung biopsy or brushings, aspiration of secretions, and delivery of pharmacological agents.
  • bronchospasm A complication of bronchoscopy, and thus an impediment to the successful completion of the procedure, is bronchospasm. Patients with a prior history of bronchospasm are particularly at risk for acute enhancement of spasm. Thus, S-nitrosothiols may also be used to relax airway smooth muscle and eliminate bronchoscopy-induced bronchospasm.
  • gastrointestinal smooth muscle refers to smooth muscle which is contained in all areas of the gastrointestinal tract. Such areas include, but are not limited to, the esophagus, duodenum, sphincter of Oddi, biliary tract, ileum, sigmoid colon, pancreatic duct and common bile duct.
  • S-nitrosothiols may be used for the treatment or prevention of gastrointestinal disorders. Disorders of the gastrointestinal tract include achalasia (spasm of the lower esophageal sphincter), diarrhea, dumping syndrome, and irritable bowel.
  • An additional embodiment of the invention relates to the administration of S-nitrosothiols to alleviate contraction or spasm of gastrointestinal smooth muscle, and thus facilitate successful completion of endoscopic procedures.
  • Contraction or spasm of gastrointestinal smooth muscle imposes a technical obstacle which must frequently be overcome in order to enable the clinician to successfully perform endoscopic procedures.
  • endoscopic procedures refers to those diagnostic procedures which utilize an instrument which is introduced into the gastrointestinal tract to provide direct visualization of the gastrointestinal tract, for examination and therapeutic purposes. Such purposes include direct visualization, biopsy, access to the common bile duct, fluid aspiration and removal of foreign bodies, polyps, and other lesions.
  • An example of a particular endoscopic procedure is esophagogastro-duodenoscopy, which is utilized for examination of the esophageal lumen, stomach and duodenum.
  • ERCP endoscopicretrograde cholangiopancreatography
  • ERCP endoscopicretrograde cholangiopancreatography
  • nitroglycerin is significantly less effective as a smooth muscle relaxant than S-nitrosothiols, and produces systemic side effects, the most significant of which is hypotension. It is therefore, not used clinically.
  • a topical smooth muscle relaxant which could be directly instilled into the various regions of the gastrointestinal tract to facilitate both diagnostic and therapeutic endoscopic procedures.
  • the relaxant effects were temporary (lasting only for the duration of the procedure), completely reversible and produced no change in systemic blood pressure, heart rate or oxygen saturation.
  • the same type of effects would occur with the use of other cell impermeable S-nitrosothiols, such as S-nitroso-glutathione.
  • S-nitrosothiols obviates the need for sphincterotomy, a procedure which substantially increases the morbidity and mortality of ERCP.
  • administration of S-nitrosothiols aids in the cannulation and manipulation of the pancreatic duct and biliary tract during therapeutic procedures such as gall bladder cannulation, bile duct stone removal and stint placement, and decreases the incidence of post-ERCP complications, such as pancreatis and cholangitis.
  • Another use of S-nitrosothiols involves the intraoperative injection of these compounds into the gall bladder prior to cholecystectomy to alleviate cystic duct spasm.
  • S-nitrosothiols may also be administered to treat or prevent any other technical problems associated with endoscopy which are known to those in the medical art.
  • Another embodiment of the invention relates to administration of a therapeutically effective amount of an S-nitrosothiol compound to relax corpus cavernosum smooth muscle.
  • corpus cavernosum refers to two areas of smooth muscle which lie side by side on the dorsal aspect of the penis, and together with the corpus spongeosum that surrounds the urethra, constitute erectile tissue.
  • This erectile tissue consists of an irregular sponge- like system of vascular spaces interspersed between arteries and veins. Erection occurs when cavernosa smooth muscle relaxation causes a decease in arterial resistance and resulting increase in arterial blood flow to the penis.
  • Another embodiment of the invention relates to the administration of a therapeutically effective amount of an S-nitrosothiol compound for the treatment of impotence.
  • Impotence refers to a condition of male sexual dysfunction which is characterized by the inability to obtain or maintain an erection.
  • Organic causes of erectile impotence may include endocrine, drug- induced, local injury, neurologic, and vascular.
  • impotence may result from neurologic blockade caused by such drugs as antihistamines, antihypertensives, psychogenic agents, and anticholinergics.
  • Impotence may also result from neurologic disorders such as interior temporal lobe lesions, spinal cord disorders, and insufficiency of sensory input resulting from diabetic neuropathy.
  • An additional cause of impotence is insufficient blood flow into the vascular network resulting from an intrinsic defect, or from penile trauma.
  • Currently available methods for treating impotence consist largely of surgical techniques and intracavernosal injections of pharmacological agents.
  • One surgical technique involves the implantation of a penile prosthesis by inserting within the corpora, a small silastic rod.
  • this method does not produce full erection and the complication rate is high.
  • an inflatable prosthetic device may be implanted on either side of the corpora, with a connecting reservoir of material placed in the perivascular space. Erection is achieved through the use of pumps which are located in the scrotum.
  • S-nitrosothiols results in relaxation of corpus cavernosum smooth muscle, which leads to dilation of the cavernosal arteries and a concommittent increase in blood flow.
  • S-nitrosothiols provide significant advantages in the treatment of impotence over current treatment methods, because they can be administered topically, thereby eliminating the systemic side effects, significant discomfort, fibrosis, and ineffectiveness associated with the currently available, invasive methods of treatment.
  • Another embodiment of the claimed invention relates to the administration of a therapeutically effective amount of an S-nitrosothiol compound to relax bladder smooth muscle.
  • Bladder smooth muscle includes that of the bladder base, bladder body and proximal urethra.
  • S- nitrosothiols may be used for the treatment of bladder dysfunction disorders which involve relaxation of bladder smooth muscle. Such disorders include, but are not limited to, problems with bladder filling, volume and continence.
  • S-nitrosothiols may be administered to cause relaxation of urethral and bladder base smooth muscle, and thus, facilitate cystoscopic examination of the urinary tract.
  • cystoscopic examination refers to the introduction of a fiberoptic instrument through the urethra and into the bladder, to achieve visualization of the interior of the urethra and bladder for diagnostic and therapeutic purposes.
  • Another embodiment of the invention relates to the administration of a therapeutically effective amount of an S-nitrosothiol compound to relax uterine smooth muscle. Increased contractility of uterine smooth muscle precipitates premature labor.
  • an additional embodiment of the invention relates to the administration of S-nitrosothiol compounds for the treatment or prevention of premature labor.
  • S-nitrosothiols may also be used to relax fallopian tube smooth muscle.
  • Fallopian tube smooth muscle plays a role in the transport of the egg to the uterus.
  • S-nitrosothiols may be used to regulate ovum transport, or to facilitate laparoscopic examination of the fallopian tubes, or to facilitate fertilization procedures.
  • the long-chain lipophilic compounds have unique potential for NO delivery by incorporation into cell membranes, and for accessing the central nervous system (CNS).
  • CNS central nervous system
  • nitric oxide has been shown to inhibit cell death resulting from ischemic injury, as well as to possess neurotransmitter functions.
  • Membrane permeability achieved by these compounds also provides the unique potential for NO delivery in every organ system.
  • NO delivery can be regulated by the incorporation of additional functional groups into the molecule.
  • Each functional group including but not limited to nitrite, nitrate, redox metal, amine, aromatic, and basic amino acids, has its own unique functional aspects which will affect (a) a targeted site of delivery (b) rate of NO release (c) lipophilicity (d) cell permeability (e) duration of action (f) bioactivity and (g) nitrosation potential.
  • An additional embodiment of the invention relates to the administration of an S-nitrosothiol compound as part of a pharmaceutical composition, comprising a pharmaceutically acceptable carrier, to achieve the physiological effects discussed above.
  • compositions utilized in this invention can be administered by intranasal, oral, enteral, topical, sublingual, rectal, intramuscular, intravenous, or subcutaneous means.
  • the compositions may be administered by medical instrumentation including, but not limited to, bronchoscopic, endoscopic, laporascopic, and cystoscopic means.
  • topical includes administration in the form of a condom which contains the pharmaceutical composition.
  • Certain S-nitrosothiols, such as lipophilic S-nitrosothiols are especially suitable for (i.e. lipophilic) incorporation into the condom itself, to provide sustained release of the compound.
  • the compounds of this invention can be employed in combination with conventional excipients; i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or intranasal application which do not deleteriously react with the active compounds.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • particularly suitable vehicles consist of solutions
  • tablets, dragees or capsules having talc and/or a carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • a "therapeutically effective amount" of a pharmaceutical composition is an amount which is sufficient to achieve the desired pharmacological effect.
  • the dosage required to provide an effective amount of the composition will vary, depending upon die age, health, physical condition, sex, weight and extent of disease, of the recipient. Additionally, the dosage may be determined by die frequency of treatment and the nature and scope of the desired effect.
  • Glutathione, L-cysteine, DL-homocysteine, D-penicillin, hemoglobin (bovine), methylene blue and Medium 199 sets were purchased from Sigma Chemical Co., St Louis, MO.
  • N-acetylcysteine was obtained from Aldrich Chemical Co., Milwaukee, WI.
  • Captopril was kindly provided by Dr Victor Dzau.
  • Sodium nitrite, histamine and methacholine were purchased from Fisher Scientific, Fairlawn, NJ.
  • Leukotriene D 4 was purchased from Anaquest, BOC Inc., Madison, WI.
  • Antibiotic/antimycotic mixture 10,000 U/ml penicillin G sodium, 10,000 mcg/ml, streptomycin sulfate, 25 mcg/ml amphotericin B was purchased from Gibco Laboratories, Grand Island, NY. Radioimmunoassay kits for the determination of cyclic GMP were purchased from New England Nuclear, Boston, MA.
  • the trachea rings were placed in sterile Medium 199 containing 1% antibiotic/antimycotic mixture in an atmosphere of 5% CO 2 , 45% O 2 , 55% N 2 , and kept for up to 48 hours in tissue culture.
  • the experiments were also performed on human airway smooth muscle, isolated by die same method.
  • S-nitrosothiols were prepared at 25°C by reacting equimolar (100 ⁇ M) concentrations of reduced thiols with NaNO 2 in 0.5 N HCl (acidified NaNO 2 ) as described previously (Kowaluk et al., J. Pharmacol. Exp. Ther. 256: 1256- 1264 (1990); Loscalzo et al., J. Pharmacol. Exp. Ther. 249(3):726-729 (1989); and Ignarro et al., J. Pharmacol. Exp. Ther. 218(3):739-749 (1981)). Solutions turned from clear to various shades of red instantaneously upon product formation, with the notable exception of S-nitroso-penicillamine, which is green.
  • the long-carbon chain lipophilic nitrosothiols, long and short chain S- nitrosodithiols, and S-nitrosothiols with additional functional groups were synthesized by one or more of the following methods: (a) exposure to equimolar N 2 O 3 or N 2 O 4 in CCl4; (b) exposure to equimolar acidified nitrite; (c) exposure to equimolar bubbled NO gas; (d) exposure to excess cold bubbled NO 2 gas; and (e) exposure to metherolic acid or equimolar NaNO 2 diluted in methersol.
  • Trachea and aortic rings were mounted on stirrups and connected to transducers (model FOT3C Grass) with which changes in isometric tension were measured. Rings were then suspended in 10 cc of oxygenated (95 % O 2 ,
  • the rings were equilibrated for 60 minutes under a load of 1 gm and then primed twice by exposure to 100 ⁇ M methacholine. Tissues were contracted with various agonists at concentrations determined to generate 50% ( ⁇ 16% S.D.) of maximum tone, after which the effects of different tiiiols and tiieir S-nitrosylated derivatives were assessed. In selected experiments, relaxation responses were determined in the presence of hemoglobin, or after rings had been preexposed to methylene blue for 30 minutes.
  • rings were preexposed to the guanylate cyclase inhibitor, mediylene blue (10 -4 M) for 30 minutes. Tissues were then individually pulverized with a glass (s) homogenizer and centrifuged at 8000 g for 5 minutes. The clear supernatant was extracted with water-saturated eth er and assayed for cyclic GMP by radioimmunoassay. Acetylation of samples with acetic anhydride was used to increase the sensitivity of the assay and die determination of recoveries was aided by die use of [ 3 H] cyclic GMP.
  • N-acetylcysteine is a minor metabolite of cysteine that is used for its mucolytic properties in the treatment of airway obstruction. N-acetylcysteine has also received attention within the context of nitrate metabolism and undergoes S-nitrosylation in plasma upon treatment with nitroglycerin (Fung et al., J. Pharmacol. Exp. Ther.
  • the S-nitrosylated derivatives of these four sulfhydryls comprise the group of biological S-nitrosothiols under investigation.
  • Captopril and penicillamine are examples of nonbiological low molecular weight thiols, and their S-nitrosylated derivatives have been well characterized (Kowaluk et al., J. Pharmacol. Exp. Ther. 256:1256-1264
  • Figure 8 shows a comparison between die efficacy of SNOAC and isoproterenol or theophylline under identical study conditions.
  • isoproterenol was the most active relaxant, however, SNOAC was approximately SO times more active in relaxation than theophylline.
  • Hemoglobin and mediylene blue are established inhibitors of NO-induced relaxations in vascular smooth muscle (Ignarro et al., Circ. Res. 65:1-21 (1989)).
  • hemoglobin and mediylene blue each partially attenuated (only 10-20% attenuation)d ⁇ e actions of SNOAC, as evidenced by rightward shifts in the dose-effect relationships to SNOAC in their presence ( Figure 9).
  • Figure 13 demonstrates tiiat the relaxant effect of SNOAC upon human trachea is significantly greater than that of N-acetylcysteine.
  • NAC caused significant constriction of die tracheal smooth muscle, which is consistent with the fact that NAC, when given as a mucolytic agent, causes die untoward side effect of bronchospasm.
  • SNOAC not only causes relaxation of airway tissue, but also eliminates bronchospasm.
  • Figure 14 demonstrates that SNOAC and SNOGSH exert a relaxant effect on airway smooth muscle which is significandy more potent than that of theophylline, and compares favorably with that exerted by isoproterenol.
  • die relaxation response to low molecular weight S- nitrosothiols in airways differs markedly from that observed in blood vessels. In die latter case, relaxations occur slowly and persist for a much longer duration. This is most likely attributed to die inherent differences between vascular and nonvascular smooth muscle. There may be additional contributing factors responsible for this heterogeneity. Finally, any disparity among smooth muscle cells in redox state, availability of reducing equivalents, pH, oxygen tension, or any other factor that might influence die stability of the S-NO bond would be predicted to influence relaxation kinetics.
  • nitro(so)-bronchodilators may be determined by the nature of die chemical mediators contributing to bronchoconstriction.
  • S-nitrosothiols were most effective in this study against leukotriene D 4 -mediated bronchoconstriction and progressively less effective against histamine and methacholine-mediated constriction.
  • S- nitrosothiols derives from assay determinations performed in die presence and absence of HgCl 2 , the latter reagent catalyzing the hydrolysis of die S-NO bond. Confirmatory evidence for S-nitrosothiol bond formation was obtained by spectrophotometry, demonstrated by die absorption maximum of 450 nm, as shown in Figure 17. This was demonstrated using NO + equivalents in the form of SNOAC.
  • die UV spectrum of hemoglobin incubated with SNOAC shows no reaction at the redox metal (iron-binding site) of hemoglobin, over 15 minutes.
  • equimolar concentrations of hemoglobin and NaNO 2 were reacted in 0.5 N HCl, to form nitrosyl-hemoglobin, and die UV spectrum was obtained.
  • NO reacted instantaneously with the redox metal site on hemoglobin.
  • S-nitrosothiol did not react with the redox metal site of hemoglobin, but with its thiol group instead, indicates tiiat the reactive NO species donated by die S-nitrosothiol is nitrosonium or nitroxyl.
  • S-nitrosylation of hemoglobin does not result in the formation of mememoglobin and consequent impairment in hemoglobin-oxygen binding,. Furthermore, an additional experiment demonstrated that S-nitrosylation of hemoglobin causes a leftward shift in the hemoglobin-oxygen association curve, indicating an increase in oxygen binding. Thus, die reaction between S-nitrosothiols and hemoglobin not only eliminates the inhibition of oxygen binding which occurs from the reaction with NO ⁇ , but actually increases binding and oxygenation of the blood.
  • S-nitrosothiols are important intermediates in die metabolism of organic nitrates and endogenously-derived NO. Furthermore, these compounds provide greater stability, a longer half life than NO, and retain its cyclic GMP-dependent bioactivity in blood vessels.
  • S- nitrosothiols are also potent airway smooth muscle relaxants and mediate their effects through both activation of guanylate cyclase, and a cGMP-independent mechanism.
  • the results indicate that there are a number of important mediators of airway tone, including cGMP.
  • the results also demonstrate a mechanism by which die bioactivity of NO is preserved in die presence of high ambient concentrations of oxygen and reactive oxygen species and redox metals.
  • S-nitrosothiols also increase hemoglobin-oxygen binding, thus providing a means for enhancing oxygenation of the blood and oxygen transport to tissues.
  • these compounds have significant pharmacological utility for the treatment of airway obstruction, or other disorders resulting in insufficient blood oxygenation.

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Abstract

Les S-nitrosothiols exercent un puissant effet relaxant, induit à la fois par la guanylate-cyclase et par un mécanisme indépendant cGMP (guanosine-monophosphate cyclique) sur les muscles lisses. Ces types de muscles lisses se situent notamment au niveau des voies aériennes, du système gastrointestinal, de la vessie, des voies utérines et des corps caverneux. Les S-nitrosothiols peuvent donc être utilisés dans le traitement ou la prévention de troubles associés à la décontraction des muscles lisses, tels que l'obstruction des voies aériennes, et autres troubles respiratoires, le dysfonctionnement de la vessie, le travail dans l'accouchement prématuré et l'impuissance. De plus, les S-nitrosothiols peuvent être utilisés pour soulager les contractions et les spasmes des muscles lisses et pour faciliter les interventions en chirurgie instrumentale, telles que l'endoscopie, la bronchoscopie, la laparoscopie et la cystoscopie. Les S-nitrosothiols augmentent également l'affinité de liaison entre l'hémoglobine et l'oxygène, et par conséquent peuvent être utilisés pour améliorer la liaison hémoglobine - oxygène et le transport de l'oxygène dans les tissus de l'organisme.
PCT/US1992/010447 1991-12-11 1992-12-07 S-nitrosothiols utilises comme decontracturants des muscles lisses et leurs utilisations therapeutiques WO1993012068A1 (fr)

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US07/943,834 US5380758A (en) 1991-03-29 1992-09-14 S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof

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US5536241A (en) * 1990-12-05 1996-07-16 The General Hospital Corporation Methods and devices for relaxing smooth muscle contractions
US5570683A (en) * 1990-12-05 1996-11-05 The General Hospital Corporation Methods and devices for treating pulmonary vasoconstriction and asthma
WO1997009972A1 (fr) * 1995-09-15 1997-03-20 Duke University Medical Center Erythrocytes charges de s-nitrosothiol et leurs utilisations
WO1997010265A1 (fr) * 1995-09-15 1997-03-20 Duke University Medical Center Hemoglobines nitrosees et leurs utilisations therapeutiques
US5823180A (en) * 1995-04-03 1998-10-20 The General Hospital Corporation Methods for treating pulmonary vasoconstriction and asthma
US5873359A (en) * 1990-12-05 1999-02-23 The General Hospital Corporation Methods and devices for treating pulmonary vasoconstriction and asthma
WO1999016436A1 (fr) * 1997-09-30 1999-04-08 John Rhodes Compositions pharmaceutiques utilisees dans le traitement de la maladie intestinale inflammatoire et du syndrome du colon irritable
US5904938A (en) * 1995-02-16 1999-05-18 The General Hospital Corporation Treatment of vascular thrombosis and restenosis with inhaled nitric oxide
EP0941086A4 (fr) * 1996-11-01 2000-07-12 Nitromed Inc Composes nitroses et nitrosyles inhibiteurs de la phosphodiesterase, compositions comprenant ces composes et utilisations correspondantes
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USRE37234E1 (en) 1996-11-01 2001-06-19 Nitromed, Inc. Nitrosated and nitrosylated phosphodiestrase inhibitor compounds, compositions and their uses
US6294517B1 (en) 1996-02-02 2001-09-25 Nitromed, Inc. Compositions and kits comprising alpha-adrenergic receptor antagonists and nitric oxide donors and methods of use
US6323211B1 (en) 1996-02-02 2001-11-27 Nitromed, Inc. Compositions and methods for treating sexual dysfunctions
US6331543B1 (en) 1996-11-01 2001-12-18 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
WO2001052835A3 (fr) * 2000-01-18 2001-12-20 Irina Buhimschi Phagocytes de radicaux libres ou promoteurs de ces derniers utilises en tant qu'adjuvants therapeutiques pour les accouchements avant terme
US6403759B2 (en) 1996-08-02 2002-06-11 Duke University Polymers for delivering nitric oxide in vivo
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US6855691B1 (en) 1995-09-15 2005-02-15 Duke University Methods for producing and using S-nitrosohemoglobins
US6911427B1 (en) 1995-09-15 2005-06-28 Duke University No-modified hemoglobins and uses therefore
US6916471B2 (en) 1995-09-15 2005-07-12 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
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EP1420851A4 (fr) * 2001-08-02 2008-12-31 Univ Duke Utilisation d'un agent de prevention de diminution du debit sanguin en combinaison avec un gaz d'insufflation
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US9708367B2 (en) 2013-03-15 2017-07-18 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase and their uses
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