Use of glutamate 2b receptor antagonists and sigma receptor agonists as cough suppressants

Abstract

Disclosed are uses of glutamate 2b receptor antagonists and sigma receptor agonists as antitussives for treating or preventing cough. In a preferred embodiment, the glutamate 2b receptor antagonist is ifenprodil or radiprodil. Preferred sigma receptor agonists include fluvoxamine, fluoxetine, escitalopram, and donepezil.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 926,871, filed on October 28, 2019, entitled “Compositions and Methods for Treating Cough,” and U.S. Provisional Patent Application No. 62 / 943,537, filed on December 4, 2019, entitled “Compositions and Methods for Treating Cough,” the contents of which are hereby expressly incorporated by reference into this application in their entireties. Field of the Invention

[0003] The present invention relates to use of a compound for treating cough, in particular to use of a glutamate 2b receptor antagonist such as Ifenprodil and Radiprodil for treating cough.

[0004] background

[0005] A cough, also called a tussis, is a sudden, protective expulsion of air from the lungs, often accompanied by a sound. A cough may be irregular, such as when it helps clear fluid, irritants (such as air pollution), and / or foreign particles from the airways. However, a cough may become repetitive and frequent, which may indicate the presence of a disease, such as a respiratory infection or mild bronchitis. A cough may also be chronic, lasting for weeks, which may be associated with a more serious underlying medical condition, such as asthma, gastroesophageal reflux disease, nonasthmatic eosinophilic bronchitis, and upper airway cough syndrome.

[0006] A chronic (persistent) cough is one that lasts eight weeks or longer in adults or four weeks in children. A chronic cough can interrupt sleep, cause energy depletion, and in severe cases, lead to severe vomiting, dizziness, and rib fractures.

[0007] A dry, nonproductive cough is a very common symptom of IPF. At least 70%-85% of IPF patients experience a dry cough that often gets worse with exertion.

[0008] According to a recent report by Research and Markets, in the United States, cough is the most common complaint patients present to doctors and the second most common reason for general health checkups, resulting in more than 26 million visits annually.

[0009] There is currently no known cure for cough. Conventional treatment tends to focus on relieving symptoms. This includes home remedies such as drinking honey in water, over-the-counter expectorants, and cough suppressants.

[0010] The present invention provides a new use of existing drugs that are often studied and used as potential treatments for other conditions, for the treatment and / or relief of cough. Summary of the Invention

[0011] In one embodiment of the present invention, a glutamate 2b receptor (Glut2B or GluN2B) antagonist is used to treat or prevent cough in a subject. The Glut2B antagonist can be one or more of Ifenprodil, Radiprodil, Traxoprodil, Rislenmdaz, Eliprodil, Ro-25-6981, BMT-108908, EVT-101, CP101-606, MK-0657, EVT-103, and AZD 6765 (Annual Reports in Medicinal Chemistry (2012) Vol. 47: 94-103). BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Exemplary embodiments are illustrated in the reference figures of the accompanying drawings. It is intended that the embodiments and figures disclosed herein be considered illustrative rather than restrictive.

[0013] Figure 1 Schematic diagram showing the relationship and etiology of cough among central nervous system receptors and glutamate 2b receptor antagonists.

[0014] Figure 2 is a schematic diagram showing the relationship between ion channels, receptors, and glutamate 2b receptor antagonists.

[0015] Figure 3 is a bar graph summarizing the total number of coughs during a 10-minute exposure to citric acid or saline and a 5-minute recovery period in guinea pigs treated with Gefapixant or Ifenprodil compared to the vehicle group in one study.

[0016] Figure 4 is a bar graph summarizing the first cough episode in guinea pigs treated with gefapixin or ifenprodil compared with the vehicle group during a 10-minute exposure to citric acid or saline and a 5-minute recovery period in one study. Detailed Description of the Invention

[0018] The inventors have discovered that certain pharmacological compounds approved for use in other conditions can be used to prevent and / or treat cough.

[0019] Based on the description herein, it is shown that the compounds are useful for preventing and / or treating cough. When the compounds described herein are administered with citric acid to conscious guinea pigs exposed to histamine, an antitussive effect is observed.

[0020] One current therapy used to alleviate cough symptoms is the administration of the pharmacological compound gefapixen, which was used as a positive control in the experimental examples described herein.

[0021] Gefapisen, C 14 H 19 N5O4S is a non-narcotic, selective P2X3 receptor antagonist. Recent studies have shown that its use may be effective in patients with chronic cough. Further trials are underway to further evaluate the efficacy and safety of gefapiroxine in controlling cough in patients with chronic cough. The chemical structure of gefapiroxine is:

[0022]

[0023] This specification shows the effect of suppressing or alleviating cough by administering a therapeutically effective amount of Ifenprodil, Radapidil and other glutamate 2b receptor antagonists. These compounds described herein are existing drugs and are generally known for treating non-pulmonary related diseases.

[0024] The mechanisms behind its efficacy in reducing or preventing cough include the fact that the compounds target glutamate receptors and sigma 1 receptors. Similarly, the nonspecific NMDA inhibitor memantine has also shown preclinical and clinical efficacy.

[0025] Uses of Ifenprodil

[0026] Ifenprodil, 4-[2-(4-benzylpiperidin-1-ium-1-yl)-1-hydroxypropyl]phenol; 2,3,4-trihydroxy-4-oxobutanoic acid, is a selective N-methyl-d-aspartate (NMDA) receptor glutamate receptor antagonist known in the art that specifically targets NMDA-type subunit 2B (Glu2NB). Ifenprodil also exhibits agonist activity at the σ-1 receptor, a chaperone protein that is upregulated during endoplasmic reticulum stress. Ifenprodil was originally developed (in the early 1970s) as a vasodilator. Ifenprodil is currently being studied for the treatment of adolescent PTSD. The chemical structure is:

[0027]

[0028] In some embodiments tested in the Examples herein, Ifenprodil hemitartrate having the following structure was used:

[0029]

[0030] In one aspect, the present invention provides uses and methods of treating or preventing cough in a subject with Ifenprodil or a pharmaceutically acceptable variant thereof.

[0031] In one embodiment, the dosage of Ifenprodil is 0.6 to 5 mg per kg of subject per day. In a preferred embodiment, the dosage of Ifenprodil is 0.8 to 3 mg per kg of subject per day. In a further preferred embodiment, the dosage of Ifenprodil is about 1.5 mg per kg of subject per day.

[0032] Ifenprodil or its pharmaceutically acceptable variant can be administered to a subject orally, intravenously or in a manner known in the art. Ifenprodil or its pharmaceutically acceptable variant can also be administered together with one or more pharmaceutically acceptable excipients.

[0033] Uses of radilalide

[0034] Radiprodil, 2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]-2-oxo-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide, is known in the art as an NMDA receptor antagonist. It has been used in trials to treat infantile spasms (IS) and diabetic peripheral neuropathic pain. The chemical structure of radiprodil is:

[0035]

[0036] In one aspect, the present invention provides uses and methods of using radiprodil or a pharmaceutically acceptable variant thereof to treat or prevent cough in a subject.

[0037] In one embodiment, the dosage of radiprodil is 1.6 to 3.3 mg per kg of subject per day. In a preferred embodiment, the dosage of radiprodil is about 2.5 mg per kg of subject per day. In a further preferred embodiment, the dosage of radiprodil is about 2.25 mg per kg of subject per day.

[0038] Radapidil or its pharmaceutically acceptable variants can be administered to a subject orally, intravenously or in a manner known in the art. Radapidil or its pharmaceutically acceptable variants can also be administered together with one or more pharmaceutically acceptable excipients.

[0039] Uses of glutamate 2b receptor antagonists

[0040] In one embodiment of the present invention, a glutamate 2b receptor (Glut2B or GluN2B) antagonist is used to treat or prevent cough in a subject. The Glut2B antagonist can be one or more of Ifenprodil, Radaprol, Traxoprolol, Lilenenda, Elirodil, Ro-25-6981, BMT-108908, EVT-101, CP101-606, MK-0657, EVT-103, and AZD 6765 (Annual Reports in Medicinal Chemistry (2012) Vol. 47: 94-103).

[0041] In another aspect of the present invention, Ifenprodil is known to exhibit NDMA receptor antagonism (GluN1, more specifically GluN2B subunit) and σ receptor agonist (more specifically subtype 1) activity. σ receptors are intracellular chaperones that reside in the endoplasmic reticulum of cells. Therefore, molecules with similar activity have anti-fibrotic effects and treat IPF. IPF may or may not be accompanied by cough. Previous studies on Ifenprodil and IPF used a mouse bleomycin model. Because mice do not have a cough reflex, nothing is known about the effect of Ifenprodil on cough (if any). Representative σ receptor agonists include selective serotonin reuptake inhibitors (SSRIs), such as fluvoxamine, fluoxetine, excitalpram, and donepezil (J. Pharmacological Sciences (2015) 127: 6-9).

[0042] Combination use

[0043] In another aspect, the present invention provides uses and methods of treating or preventing cough in a subject using a combination of one or more of Ifenprodil, Radapralid, Traxoprold, Lilenanda, Elirodil, Ro-25-6981 and BMT-108908, EVT-101, CP101-606, MK-0657, EVT-103, and AZD 6765. In another aspect, the present invention provides uses and methods of treating or preventing cough in a subject using one or more of Ifenprodil, Radapralid, Traxoprold, Lilenanda, Elirodil, Ro-25-6981 and BMT-108908, EVT-101, CP101-606, MK-0657, EVT-103, and AZD 6765, in combination with one or more of dexamethasone, pirfenidone, and nintedanib.

[0044] The term "therapeutically effective amount" as used herein refers to the amount of active ingredient sufficient to confer the desired preventive or therapeutic effect in the subject being treated. In some embodiments, the effective amount is determined, for example, based on the route and frequency of administration, the species and weight of the subject receiving the pharmacological compound.

[0045] In some embodiments, an effective amount of a pharmacological compound is formulated with a pharmaceutically acceptable carrier and administered to a subject. As used herein, the term "pharmaceutically acceptable" refers to a carrier known in the art that is compatible with the pharmacological compound and is safe for the subject being treated. In some embodiments, a pharmaceutically acceptable carrier is determined by one skilled in the art by evaluating, for example, the solubility of the pharmacological compound in the carrier.

[0046] Embodiments of the present invention are further described with reference to the following examples, which are illustrative rather than limiting in nature.

[0047] Examples - Materials and Methods

[0048] The guinea pig species used in one study were 24 male Dunkin Hartley guinea pigs, each weighing between 300 and 350 g, provided by Marshall Bioresources Ltd, UK.

[0049] Guinea pigs were housed in pens (11125cm 2 ) with a 12-hour light / dark cycle. Room temperature and humidity were maintained within home office guidelines (17-24°C and 40-70%, respectively). Environmental enrichment was also provided in all enclosures. Guinea pigs were allowed ad libitum access to a standard chow diet. Water was also available ad libitum from bottles. A 7-day acclimatization period was allowed before the start of experimental procedures.

[0050] Animals were observed once daily in the morning throughout the study. During treatment, animals were observed every 15–30 minutes. Any animal showing signs of distress exceeding the limits of the UK Home Office project licence was sacrificed and the sponsor monitor was notified.

[0051] The following guidelines (provided by the UK Home Office) are used to evaluate non-specific or unexpected adverse reactions in animals subjected to standardized procedures in this study. They are related to the procedure, the dose of test compound or control drug administered. Animals that exhibit two or more of any of the following restrictive clinical signs equivalent to the severity limits of the protocol will be removed from the study and euthanized at the establishment using the Schedule 1 method (usually cervical dislocation). If an animal reaches one or both of the first two signs, with or without any other signs, the animal will be removed from the study and sacrificed at the establishment using the Schedule 1 method. Animals exposed to severe fighting injuries will also be removed from the study and sacrificed at the establishment using the Schedule 1 method.

[0052] Limiting clinical signs include:

[0053] Weight loss greater than 20% of the highest measured individual body weight.

[0054] Food and water consumption less than 40% of normal for 3 consecutive days or anorexia (complete loss of appetite for 72 hours).

[0055] Obvious piloerection and other signs of dehydration, such as wrinkling of the skin.

[0056] Unresponsive to activity and provocation.

[0057] ·Continuously hunching your back (stiffness).

[0058] Worry – Continuous vocalization.

[0059] ·Continuous and heavy discharge from the eyes and nose.

[0060] Labored breathing.

[0061] Persistent tremors.

[0062] ·Continuous convulsions.

[0063] In this study, no animals were removed due to fighting injuries or injuries exceeding the aforementioned severity limits.

[0064] The test compounds, Ifenprodil and Gefapixen (in powder form), were prepared and formulated by initially adding the volume of 100% propylene glycol required for the final treatment buffer. Additional buffer components were added in a stepwise manner, first solutol and then captisol. The volume of each component added was equal to the volume required for the final volume of treatment buffer for the stock formulation.

[0065] Specifically, for gefapiroxen, it is 0.7 mg / mL, delivering a concentration of 3.5 mg / Kg in a dose volume of 5 mL / Kg. For ifenprodil, it is 0.3 mg / mL, delivering a concentration of 1.5 mg / Kg in a dose volume of 5 mL / Kg.

[0066] Before adding each buffer component, the test compound formulation was sonicated for 15 minutes using a Branson 1510 Sonicator. The initial formulation of test compound and gefapiroxine was then diluted with the prepared buffer vehicle to provide additional dosing formulations. The concentration was 0.01 to 0.2 mg / ml, preferably 0.06 mg / mL, delivering a 0.3 mg / kg dose in a 5 mL / kg dose volume.

[0067] The final test compound buffer vehicle consisted of a 10:10:80 mixture of propylene glycol:20% solutol in PBS:5% sulfobutylcyclodextrin (captisol) in PBS.

[0068] The vehicle was prepared by adding 20% ​​sol alcohol in PBS to 100% propylene glycol, followed by 5% sulfobutyl cyclodextrin in PBS. The final vehicle formulation was a 10:10:80 mixture of propylene glycol, 20% sol alcohol, and 5% sulfobutyl cyclodextrin. Thus, in every 1 mL of vehicle, there would be 0.1 mL of 100% propylene glycol, 0.1 mL of 20% sol alcohol, and 0.8 mL of 5% sulfobutyl cyclodextrin.

[0069] All final test and control formulations were sonicated for 30 minutes prior to dosing to create a homogenous suspension or to ensure that the formulation was visibly dissolved.

[0070] Prior to exposure to the cough agent (citric acid), animals were first pretreated with vehicle, test compound, or gefapixel (5 mL / Kg, po) using the amounts listed below in Table 1. In each case, the route of administration of treatment was oral.

[0071] Table 1

[0072]

[0073] Animals receiving gefapiroxine (3.5 mg / kg) were dosed 2 hours prior to cough agent exposure. Animals receiving ifenprodil (1.5 mg / kg) were dosed 30 minutes prior to cough agent exposure.

[0074] Ten minutes before cough assessment, each animal was placed individually into a custom-made exposure chamber with airflow provided by a nebulizer at 2 L / min and allowed to acclimate to its new environment.

[0075] Following an acclimation period, each animal was then exposed to 1 M citric acid aerosol for 10 minutes using an ultrasonic nebulizer (Aerogen) set at a nominal liquid consumption rate of 0.6 mL / min.

[0076] Coughs and sneezes induced by 1 M citric acid aerosol for 10 minutes and the subsequent 5 minutes of observation were manually recorded to monitor the animal's well-being. This data was also used to provide a backup dataset for the dataset obtained from airflow pressure changes recorded on the data acquisition system (Powerlab), which was used to ensure accurate differentiation between coughs and sneezes. Coughing episodes, number and frequency of coughs, and sneezing data were analyzed.

[0077] At the end of each experiment, animals were immediately euthanized with an overdose of pentobarbital.

[0078] The following measurements and assessments were taken for each guinea pig:

[0079] The average total number of cough induced episodes in each treatment group

[0080] The average first cough episode in each group

[0081] The average number of coughs per minute during citric acid exposure in each treatment group

[0082] Statistical analysis of differences between groups was performed by one-way analysis of variance (ANOVA). In the event of significant differences in the means of the different treatment levels, comparisons with the citric acid vehicle group were performed using Dunnett's test. p < 0.05 was considered statistically significant.

[0083] result

[0084] Total coughs

[0085] Figure 3 The total number of coughs in guinea pigs following treatment with gefapixen (3.5 mg / Kg, po), ifenprodil (1.5 mg / Kg, po), or vehicle (5 mL / Kg, po) during a 10-minute exposure to citric acid (1 M) or saline and a 5-minute recovery period was summarized.

[0086] Each column represents the mean, and the vertical bar represents the se mean (n=6 per group). The total number of coughs in animals treated with test compound exposed to citric acid was compared to vehicle control animals using ANOVA followed by Dunnett's post hoc test (*), where *P<0.05, **P<0.01.

[0087] The raw data are provided in Appendix A below. The vehicle group experienced an average of 29.5 coughs per animal. The gefapiroxine-treated group experienced an average of 23.67 coughs per animal. Notably, the ifenprodil-treated group experienced an average of 17.17 coughs per animal.

[0088] First coughing attack

[0089] Figure 4 The time to first coughing episode during 10 min exposure to citric acid (1 M) or saline and 5 min recovery in guinea pigs following treatment with gefapiroxine (3.5 mg / Kg, po), ifenprodil (1.5 mg / Kg, po), or vehicle (5 mL / Kg, po) is summarized.

[0090] Each column represents the mean and the vertical bars represent the se mean (n=6 per group).The first cough episode in test compound treated animals was compared to vehicle control animals in citric acid exposed animals using ANOVA followed by Dunnett's post hoc test (*).

[0091] The raw data are provided in Appendix A below. The duration of the first cough attack in the vehicle group was 34.2 seconds. The duration of the first cough attack in the gefapiroxine-treated group was 49.7 seconds. Notably, the duration of the first cough attack in the ifenprodil-treated group was 59.8 seconds.

[0092] Total number of sneezes

[0093] The raw data are provided in Appendix B below. The vehicle group had an average of 5.17 sneezes per animal. The gefapiroxine-treated group had an average of 3.17 sneezes per animal. The ifenprodil-treated group had an average of 3.33 sneezes per animal.

[0094] in conclusion

[0095] In conclusion, oral administration of Radprodil and / or other glutamate 2b receptor antagonists, particularly Ifenprodil, showed efficacy in preventing and / or alleviating cough.

[0096] In particular, ifenprodil (1.5 mg / kg) showed a 42% reduction in mean cough frequency compared to untreated controls (p < 0.01). Gefapixen (3.5 mg / kg) showed a 20% reduction in mean cough frequency compared to untreated controls (p < 0.05). Both ifenprodil (59.8 seconds) and Gefapixen (49.7 seconds) showed a delay in the onset of the first cough compared to controls (34.2 seconds).

[0097] Throughout the following description, specific details are set forth to provide a more thorough understanding for those skilled in the art. However, well-known elements may not be shown or described in detail to avoid unnecessarily obscuring the present disclosure. Therefore, the description and drawings are to be regarded as illustrative rather than restrictive.

[0098] Although a number of exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize certain modifications, permutations, additions, and sub-combinations thereof. It is therefore intended that the following appended claims and the claims introduced below be interpreted as including all such modifications, permutations, additions, and sub-combinations consistent with the broadest interpretation of the entire specification.

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

Claims

1. Use of Ifenprodil in preparing a medicament for treating or preventing a subject's cough.

2. The use according to claim 1, wherein the amount of Ifenprodil is 0.1 to 5 mg per kg of the subject.

3. The use according to claim 1, wherein the amount of Ifenprodil is 0.5 to 3 mg per kg of the subject.

4. The use according to claim 1, wherein the amount of Ifenprodil is about 1.5 mg per kg of the subject.

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