EP4622637A1

EP4622637A1 - 4(rs)-4-f4-neuroprostane derivatives (4-f4t-neurop) and their use in treating ventilator induced diaphragmatic dysfunction and other diseases

Info

Publication number: EP4622637A1
Application number: EP23812924.1A
Authority: EP
Inventors: Alain Lacampagne; Jean-Yves Le Guennec; Thierry Durand; Valérie BULTEL-PONCE; Jérôme ROY; Stephan MATECKI; Haikel DRIDI; Alexandre Guy; Camille OGER; Jean-Marie GALANO
Original assignee: Centre National de la Recherche Scientifique CNRS; Institut National de la Sante et de la Recherche Medicale INSERM; Centre Hospitalier Universitaire de Montpellier; Ecole Nationale Superieure de Chimie de Montpellier ENSCM; Universite de Montpellier
Current assignee: Centre National de la Recherche Scientifique CNRS; Institut National de la Sante et de la Recherche Medicale INSERM; Centre Hospitalier Universitaire de Montpellier; Ecole Nationale Superieure de Chimie de Montpellier ENSCM; Universite de Montpellier
Priority date: 2022-11-24
Filing date: 2023-11-23
Publication date: 2025-10-01
Also published as: KR20250129659A; JP2025539852A; CN120282779A; WO2024110592A1

Abstract

Respiratory muscle contractile inactivity during mechanical ventilation (MV) induces diaphragm muscle weakness, a condition referred to as ventilator-induced diaphragm dysfunction (VIDD). Among the different hypothesis to explain VIDD, one involves the remodeling of the sarcoplasmic reticulum (SR) calcium release channel/ryanodine receptors (RyR1) in the diaphragm as a proximal mechanism of VIDD. The inventors have developed novel derivatives which prevent with a high efficiency VIDD both in a murine and porcine model of VIDD. This effect is associated with a normalization of RyR function. The present invention thus relates to novel compounds and their use in the treatment of diseases associated with Ryanodine Receptor (RyR) dysfunction.

Description

NOVEL COMPOUNDS FOR THE TREATMENT OF DISEASES ASSOCIATED WITH RYANODINE RECEPTOR (RyR) DYSFUNCTION FIELD OF THE INVENTION: The present invention relates to novel compounds, their process of preparation and their use in the treatment of diseases associated with Ryanodine Receptor (RyR) dysfunction. BACKGROUND OF THE INVENTION: Skeletal muscle contraction is activated by sarcoplasmic reticulum (SR) Ca²⁺ release via ryanodine receptor calcium release channels. RyRs are channels in the SR, which open and close to regulate the release of Ca²⁺ from the SR into the intracellular cytoplasm of the cell. Release of Ca²⁺ into the cytoplasm from the SR increases cytoplasmic Ca²⁺ concentration. Open probability of RyRs refers to the likelihood that a RyR is open at any given moment, and therefore capable of releasing Ca²⁺ into the cytoplasm from the SR. There are three types of RyR, all of which are highly homologous: RyR1, RyR2, and RyR3. RyR1 is found predominantly in skeletal muscle as well as other tissues. The RyR1 macromolecular complex consists of a tetramer of the 560-kDa RyR1 subunit that forms a scaffold for proteins that regulate channel function including protein kinase A (PKA) and the phosphodiesterase 4D3 (PDE4D3), protein phosphatase 1 (PP1) and calstabin1. Chronic PKA hyperphosphorylation of RyR1 at Ser2843 (defined as PKA phosphorylation of 3 or 4 of the 4 PKA Ser2843 sites present in each RyR1 homotetramer) results in "leaky" channels (i.e., channels prone to opening at rest), which contribute to the skeletal muscle dysfunction that is associated with persistent hyperadrenergic states such as occurs in individuals with heart failure. Moreover, regulation of RyR1 by posttranslational modifications other than phosphorylation, such as by nitrosylation of free sulfhydryl groups on cysteine residues (S-nitrosylation), as well as channel oxidation, have been reported to increase RyR1 channel activity. S-nitrosylation and oxidation of RyR1 have each been shown to reduce calstabin1 binding to RyR1. Accordingly, RyR dysfunction is a hallmark of various diseases and several methods and pharmaceutical composition have been described for the treatment of said diseases, such ventilator-induced diaphragm dysfunction (VIDD) ¹. Mechanical ventilation (MV) remains the most efficient treatment for respiratory failure in intensive care units (ICU). However, the respiratory muscle contractile inactivity induced by MV (i.e., the unloading of the respiratory muscle) has various adverse cellular effects leading, in a time-dependent way, to diaphragm weakness, atrophy and injury^2-4, a pathological condition known as ventilator-induced diaphragm dysfunction (VIDD)⁵. As VIDD increases the difficulties of MV weaning⁶, with a major impact on healthcare costs⁷, the identification of the cellular pathways involved in diaphragm weakness is an important issue to identify potential therapeutic target and or pharmacological treatment. The pathophysiological mechanisms accounting for VIDD are still not fully understood but oxidative stress is considered as a major pathophysiological mechanism of VIDD ^8-11, and mitochondria are an essential source of reactive oxygen species (ROS) ^11-13. It is not known why the production of mitochondrial ROS increases after the discharge of respiratory muscles induced by MV. The energetic homeostasis imbalance with acute substrate oversupply is a potential source of mitochondrial dysfunction¹². The inventors have developed the first murine model of VIDD that exhibit after 6 hours of ventilation a 30% decrease in force production without any histological signs of damages or necrosis¹⁴. Using this model, the inventors have shown that an early alteration of Ca²⁺ homeostasis is decisive in the establishment of VIDD. This occurs via a structural and functional remodelling of type 1 sarcoplasmic reticulum calcium channels, ryanodine receptors (RyR1) induced by oxidative stress ¹⁵. This cellular pathway could be considered as a proximal mechanism of the Ca²⁺-dependent proteolysis and muscle atrophy observed in different animal models of VIDD^8,16-18 and in human patients^3-4. Interestingly, this RyR1 remodelling has been constantly observed in ventilated mice and piglet as well as in ventilated ICU patients^15,19,20, suggesting that stabilizing directly or indirectly RyR1 function represents a potential therapeutic target in VIDD. They previously reported that omega-3 fatty acid docosahaenoic acid (DHA, C22:6 n-3) could exert a cardiac anti-arrhythmic effect due to a stabilization of the cardiac isoform of ryanodine receptor, RyR2²¹. Interestingly, the active molecule was not DHA itself but a non-enzymatic metabolite of DHA (NEO-DHA)²¹, the 4(RS)-4-F4t-Neuroprostane (4F4t-NeuroP)²². WO 2015197562 described methods of treating a disease associated with a RyR dysfunction in a subject in need thereof comprising administering the subject with a therapeutically effective amount of 4F4t-NeuroP. However, the synthesis of the compound involves several steps and thus limiting its therapeutic development. There is a need to identify new compounds effective for treating disorders and diseases associated with RyR dysfunction. More particularly, a need remains to identify new agents that can be used to treat RyR-associated disorders by, for example, RyR1destabilisation. SUMMARY OF THE INVENTION: The present invention relates to novel compounds and a process for preparing said compounds. The invention also relates to methods and pharmaceutical compositions for the treatment of diseases associated with Ryanodine Receptor (RyR) dysfunction. In particular, the present invention relates to a method of treating a disease associated with a RyR dysfunction in a subject in need thereof comprising administering the subject with a therapeutically effective amount of the novel compounds according to the invention. In particular, the present invention is defined by the claims. DETAILED DESCRIPTION OF THE INVENTION: The inventors designed derivatives of 4(RS)-4-F_4t-Neuroprostane (4-F_4t-NeuroP). said derivatives are easier to synthetize with fewer reaction steps as compared to 4-F4t-NeuroP. For instance, compound 17,18,19,20,21,22-hexanor-4(RS)-4-F_4t-NeuroP (VB558) can be obtained in only 17 steps (24 steps for 4-F_4t-NeuroP). The inventors surprisingly found that the novel compounds prevent with a high efficiency VIDD both in a murin and porcin model of VIDD. This effect is associated with a normalization of RyR function. A first object of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in a method for treatment of the human or animal body, R₁ represents H or OH, R2 represents a linear C1-C10 alkyl group, or a C2-C10 alkenyl group, with the provisio that when R₂ represents , R₁ represents H. A second object of the present invention is a method of treating a disease associated with a RyR dysfunction in a subject in need thereof comprising administering the subject with a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof: R₁ represents H or OH, R2 represents a linear C1-C10 alkyl group, or a C2-C10 alkenyl group, with the provisio that when R₂ represents , R₁ represents H. In other words, the second object of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined herein for use for treating a disease associated with a RyR dysfunction in a subject in need thereof. With “linear C₁-C₁₀ alkyl group” is meant a group chosen from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl. The linear alkyl group is in particular ethyl. With “linear C₂-C₁₀ alkenyl group” is meant a linear C₂-C₁₀ alkyl group comprising one or more double bonds in its chain. By the expression “C₂-C₁₀ alkenyl group” should also be understood a C2-C8 alkenyl group, a C2-C6 alkenyl group, a C2-C4 alkenyl group, a C4-C10 alkenyl group, a C₆-C₁₀ alkenyl group, a C₈-C₁₀ alkenyl group or a C₄-C₈ alkenyl group. As defined herein, the term “pharmaceutically acceptable salt” is intended to mean salts which are pharmaceutically acceptable, and which possess the desired pharmacological activity of the parent compound. Such salts are compounds in which the acid proton present in the parent compound is either replaced by a metal ion, for example, an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or is coordinated with a pharmaceutically acceptable organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. In a particular embodiment, the alkenyl group comprises 1 or 2 double bonds. In particular, the double bonds in R₂ are separated from the double bond to which R₂ is attached by a -CH2- group and/or are separated from each other by a -CH2- group if the number of double bonds in R₂ is 2. According to a preferred embodiment, the double bond(s) comprised in said alkenyl group of R2 are in the Z-configuration. According to a preferred embodiment, the invention relates to a method as previously described, wherein the compound of Formula I is such that R2 is a group chosen from a group of Formulae a, b and c: . The compound of Formula I comprises several asymmetric carbon atoms in its structure. The asymmetric carbon atoms comprised in the five-membered ring (carbons 7, 8, 10 (in case R1 = OH) and 11) preferably are as shown in the structure above. In a particular embodiment, the compound of Formula I has a diastereomeric excess, in relation to the carbon atoms comprised in the five-membered ring (carbons 7, 8, 10 (in case R1 = OH) and 11) of more than 90%, in particular of more than 95%. In another particular embodiment, the compound of Formula I has enantiomeric excess, in relation to the carbon atoms comprised in the five-membered ring (carbons 7, 8, 10 (in case R1 = OH) and 11) of more than 90%, in particular of more than 95%. The asymmetric carbon atom 4, at the γ-position relative to the carboxylic acid, can be in the R or S configuration, or can be a mixture of R and S configurations. According to an embodiment of the present invention, the asymmetric carbon atom at the γ- position relative to the carboxylic acid is a mixture of R and S configurations, said compound of Formula I being a mixture of diastereoisomers. In an advantageous embodiment, the compound of Formula I, is chosen from: , said compound of Formula I having the structure of Formula II, Formula III, Formula IV, Formula S-IV or Formula R-IV The compound of Formula II, 17,18,19,20,21,22-hexanor-4(RS)-4-F_4t-NeuroP (VB558), is a shorter derivative of 4-F_4t-NeuroP, comprising an alkenyl chain of 5 carbon atoms, having 1 double bond in the Z-configuration (R1 is -OH and R2 is a group of Formula a (ethyl), in relation to Formula I). In a particular embodiment, when the compound is a compound of Formula II, the asymmetric carbon atom at the γ-position relative to the carboxylic acid is a mixture of R and S configurations, said compound of Formula II being a mixture of diastereoisomers, wherein the diastereomeric excess is in particular lower than 95%, more in particular lower than 90%. The compound of Formula III, 20,21,22-trinor-4(RS)-4-F_4t-NeuroP (VB574), is a shorter derivative of 4-F_4t-NeuroP, comprising an alkenyl chain of 8 carbon atoms, having 2 conjugated double bonds in the Z-configuration (R₁ is -OH and R₂ is a group of Formula b, in relation to Formula I). The compound of Formula IV is a monohydroxylated derivative of 4-F_4t-NeuroP, wherein the 5-membered ring is substituted by 1 hydroxyl substituent. The compound of Formula IV further comprises an alkenyl chain of 11 carbon atoms, having 3 conjugated double bonds in the Z- configuration (R₁ is -H and R₂ is a group of Formula c, in relation to Formula I). The compound of Formula S-IV (VB581) is a specific diastereoisomer of compound IV, wherein the carbon atom on the γ-position of the carboxylic acid function is in the (S)- configuration. The compound of Formula R-IV (VB582) is a specific diastereoisomer of compound IV, wherein the carbon atom on the γ-position of the carboxylic acid function is in the (R)- configuration. According to a preferred embodiment, the compound of Formula I has the structure of Formula II as defined above, i.e., is 17,18,19,20,21,22-hexanor-4(RS)-4-F4t-NeuroP (VB558). In particular embodiments, the compounds of the present invention are suitable for stabilizing the complex calstabin1/RyR1. As used herein, the term “subject” denotes a mammal, such as a rodent, a feline, a canine, and a primate. Preferably, a subject according to the invention is a human. As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular interval, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]). As used herein the term " diseases associated with RyR dysfunction" means any disorder and disease that can be treated and/or prevented by modulating the RyR receptors that regulate calcium channel functioning in cells. Diseases associated with RyR dysfunction have been well documented and a person skilled in the art can readily identify such diseases. For instance, a review article by Kushnir et al (Mol. Cell. Res., 2018, 1865, p.1687-1697) discloses the relationship between specific diseases and RyR dysfunction. In addition, it can be readily determined experimentally if a disorder or disease is associated with RyR dysfunction. Typically, in order to establish the link between a disease and RyR dysfunction, 2 tests can be performed, individually, but preferably both (Matecki et al., PNAS, 2016, 113(2), p.9069-9074 and J. Muscle Res Cell Motil., 2017, 38, p.17-24). A first test relies on an RyR1 immunoprecipitation technique, allowing to identify a “biochemical signature” of leaky RyR1 channels, and allowing to establish a correlation between a specific disease and an RyR dysfunction. A second test relies on an electrophysiological technique, whereby single channel currents are recorded in order to determine the open probability of RyR. The measurement involves an experimental setup, whereby RyR channels are incorporated in lipid bilayers. The RyR channels were obtained by biopsy, and subsequent preparation of an SR-vesicle. Single channel currents were recorded using a Bilayer clamp BC-535 amplifier. Thus, "diseases associated with RyR dysfunction" include, without limitation, cardiac disorders and diseases, skeletal muscular disorders and diseases, cognitive disorders and diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome. In some embodiments, the disorder or disease is associated with an abnormal function of RyR1. In some embodiments, the method of the present invention is particularly suitable for treating a disease selected from the group consisting of cardiac disorders and diseases, muscle fatigue, musculoskeletal disorders and diseases, Central Nervous System (CNS) disorders and diseases, cognitive disorders, bone disorders and diseases, malignant hyperthermia, diabetes, sudden cardiac death, and sudden infant death syndrome, or for improving cognitive function. Cardiac disorders and diseases include, but are not limited to, irregular heartbeat disorders and diseases, exercise-induced irregular heartbeat disorders and diseases, heart failure, congestive heart failure, chronic heart failure, acute heart failure, systolic heart failure, diastolic heart failure, acute decompensated heart failure, cardiac ischemia/reperfusion (I/R) injury (including I/R injury following coronary angioplasty or following thrombolysis during myocardial infarction (MI)), chronic obstructive pulmonary disease, and high blood pressure. Irregular heartbeat disorders and diseases include, but are not limited to atrial and ventricular arrhythmia, atrial and ventricular fibrillation, atrial and ventricular tachyarrhythmia, atrial and ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia (CPVT), and exercise- induced variants thereof. In some embodiments, the method of the present invention is particularly suitable for the treatment of muscular diseases that include, but are not limited to, skeletal muscle fatigue, central core diseases, exercise-induced skeletal muscle fatigue, bladder disorders, incontinence, sleep apnea, age-associated muscle fatigue, sarcopenia, congenital myopathies, cancer cachexia, myopathy with cores and rods, mitochondrial myopathies [e.g., Kearns-Sayre syndrome, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) syndrome, and MERRF (myoclonus epilepsy with ragged-red fibers) syndrome], endocrine myopathies, muscular glycogen storage diseases [e.g., Pompe's disease, Andersen's disease, and Cori's diseases], myoglobinurias [e.g., McArdle's disease, Tarui disease, and DiMauro disease], dermatomyositis, myositis ossificans, familial periodic paralysis, polymyositis, inclusion body myositis, neuromyotonia, stiff-man syndrome, malignant hyperthermia, common muscle cramps, tetany, myasthenia gravis, and muscular dystrophy. Examples of muscular dystrophy include, but are not limited to, Duchenne Muscular Dystrophy (DMD), Becker's Muscular Dystrophy (BMD), Limb Girdle Muscular Dystrophy (LGMD), Congenital Muscular Dystrophy (CMD), distal muscular dystrophy, facioscapulohumeral dystrophy, myotonic muscular dystrophy, Emery-Dreifuss muscular dystrophy, and oculopharyngeal muscular dystrophy. Congenital muscular dystrophy as used herein refers to muscular dystrophy that is present at birth. CMD is classified based on genetic mutations: 1) genes encoding for structural proteins of the basal membrane or extracellular matrix of the skeletal muscle fibres; 2) genes encoding for putative or demonstrated glycosyltransferases, that in turn affect the glycosylation of dystroglycan, an external membrane protein of the basal membrane; and 3) other. Examples of CMD include, but are not limited to Laminin-α2-deficient CMD (MDC1A), Ullrich CMG (UCMDs 1, 2 and 3), Walker-Warburg syndrome (WWS), Muscle-eye-brain disease (MEB), Fukuyama CMD (FCMD), CMD plus secondary laminin deficiency 1 (MDC1B), CMD plus secondary laminin deficiency 2 (MDC1C), CMD with mental retardation and pachygyria (MDC1D), and Rigid spine with muscular dystrophy Type 1 (RSMD1). In some embodiments, the method of the present invention is particularly suitable for treating of cognitive disorders. Cognitive disorders, diseases or dysfunction include, but are not limited to, Alzheimer's Disease, memory loss, age-dependent memory loss, post-traumatic stress disorder (PTSD), a neuropathy and seizures. The cognitive dysfunction may be stress- related, age-related or a combination thereof. Alternatively, the cognitive dysfunction is associated with a disease or disorder, including but not limited to, Alzheimer's disease (AD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), Parkinson's Disease (PD), post-traumatic stress disorder (PTSD), Huntington's disease, Rhett Syndrome, Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS or motor neuron disease), Schizophrenia, Bipolar disorder; and major depression. In some embodiments, the method of the present invention is particularly suitable for the treatment of ventilator-induced diaphragmatic dysfunction. As used herein, the expression “ventilator-induced diaphragmatic dysfunction” or “VIDD” has its general meaning in the art and refers to the condition wherein diaphragmatic atrophy and contractile dysfunction occur after prolonged controlled mechanical ventilation 24.Ventilator-induced diaphragmatic dysfunction may result from prolonged controlled mechanical ventilation (MV), e.g., greater than 12 hours. However, such prolonged MV is not limited to any specific time-length. For example, in some embodiments, prolonged MV includes a time from at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 50, or 100 hours, to from at least about 1, 10, 20, 50, 75, 100 or greater hours, days, or years. In another embodiment, prolonged MV includes a time from at least about 5, 6, 7, 8, 9 or 10 hours, to from at least about 10, 20 or 50 hours. In some embodiments, prolonged MV is from about at least 10-12 hours to any time greater than the 10-12 hours period. In some embodiment, the subject needs artificial respiratory support because he suffers from respiratory failure and/or heart failure, which can be aggravated by sepsis, metabolic disorder, neuromuscular diseases, or surgery along with post-surgical recovery. Typically, the subject suffers from a disease for which the worsening of the symptoms has led the subject to need artificial respiratory support (i.e. mechanical ventilation). For example, some lung diseases, such as Chronic Obstructive Pulmonary Disease (COPD), pneumonia, sepsis (including severe sepsis and septic shock), Acute Respiratory Distress Syndrome (ARDS), Severe Acute Respiratory Syndrome (SARS) and cystic fibrosis (CF) usually require some form of ventilation assistance in order to clinically improve the subject. Most patients with severe coronavirus disease 2019 (COVID-19) are associated acute respiratory failure and need mechanical ventilation. The COVID-19 is a respiratory syndrome that manifests a clinical pathology resembling mild upper respiratory tract disease (common cold-like symptoms) and occasionally severe lower respiratory tract illness and extra- pulmonary manifestations leading to multi-organ failure and death. Among the more than 430 million people infected worldwide with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many have required mechanical ventilation. It is estimated that Five percent of patients infected with SARS-CoV-2 require advanced respiratory support³⁷. Thus, in some embodiments the subjects suffer from COVID-19. In some embodiments the subject suffers from a trauma. Pulmonary dysfunction in trauma patients is multifactorial and may be the result of direct contusion of the lung tissue, lung injury by fractured ribs, loss of chest wall function, fat embolism to the lung from long bone fractures, aspiration of blood or gastric contents and the consequences of the activation of the systemic inflammatory response syndrome (SIRS) of shock, reperfusion, and transfusion therapy. In some embodiments, the compound of Formula I is administered before MV, immediately after MV initiation, during MV, and/or immediately after MV. In some embodiments, administration of the the compound of Formula I according to the invention is provided at any time during MV. The compound of Formula I according to the invention is also suitable for preventing risks associated with ventilator-induced diaphragmatic dysfunction. Risks associated with ventilator dependence include increased discomfort and risk of secondary diseases for the patient (such as pneumonia, pulmonary fibrosis, aspiration, acute renal failure, cardiac arrhythmias, sepsis, vocal fold dysfunction, and acute lung injury secondary to barotrauma or volotrauma), increased morbidity and mortality, high health care costs, and longer treatment duration times. Although patients with chronic ventilator dependency (CVD) comprise only 5% to 10% of patients in intensive care units, they consume approximately 50% of all ICU resources, as measured in staff time and equipment usage. Specifically, it has been estimated that weaning patients consumed about 41% of total ventilation time in intensive care unit patients. The economic cost of long term MV dependence is enormous. Episodes of long term MV dependency can financially devastate families and health care institutions and are a financial drain on private insurers and government health care resources. According to the invention, the compound of Formula I is administered in a therapeutically effective amount. By a "therapeutically effective amount" is meant a sufficient amount of the compound of Formula I to treat the target disease at a reasonable benefit/risk ratio applicable to any medical treatment. It is understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. In particular, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, in particular from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day. The compound of Formula I is typically combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to be administered in the form of a pharmaceutical composition. "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms. Typically, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The antibody can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active antibody in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Thus, a third object of the present invention relates to a pharmaceutical composition comprising a compound of Formula I as previously defined, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A fourth object of the present invention is a novel compound of Formula IA or a pharmaceutically acceptable salt thereof: R₁ represents H or OH, R2 represents a linear C1-C10 alkyl group, a C2-C7 alkenyl group comprising 1 double bond, or a C₂-C₁₀ alkenyl group comprising 2 double bonds, with the provisio that when R2 represents , R1 represents H. In one embodiment, R₂ is a group chosen from a group of Formulae a, b and c: . The novel compound is in particular chosen from chosen from: , said compound of Formula IA having a structure of Formula IIA, Formula IIIA, Formula IVA, Formula S-IVA, or Formula R-IVA. A fifth object of the present invention relates to a compound of Formula IA as defined above for use in a method for treatment of the human or animal body. A sixth object of the present invention relates to a pharmaceutical composition comprising a compound of Formula IA as previously defined, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A seventh object of the present invention is a process for preparing a compound of Formula I, or a compound of Formula IA, as previously defined, wherein the process comprises: a step A of oxidation of an alcohol of Formula V to give an aldehyde of Formula VI, R₃ being an group, a group, more in particular a t-butyldimethylsilyl protecting group, R4 being methyl or ethyl, R₅ being H or OR₃, wherein R₃ is as defined above. a step B of olefination of the aldehyde of Formula VI to give an olefin of Formula VII, R3, R4 and R5 as R2 being as previously defined for Formula I. a step C of deprotection of the hydroxyl groups in Formula VII to give an ester of Formula VIII R₄ and R₅ being as step R₁ and R₂ being as previously defined for Formula I. a step D of hydrolysis of the ester of Formula VIII to give a compound of Formula I, R₄ being as defined in step A, R1 and R2 being as previously defined. In the process according to the present invention, the protecting group R₃ is chosen such that it is not removed under the reaction conditions of step A and step B. In addition, the protecting group R3 is chosen so that said group can be selectively removed in the presence of the ester (R₄ = methyl or ethyl). In a preferred embodiment, the protecting group R3 is selected from silyl protecting groups, preferably tert-butyldimethylsilyl (tBDMS) or triisopropylsilyl (TIPS), in particular tert-butyldimethylsilyl. Step A - oxidation In the process of the invention, the selective oxidation of the hydroxyl group into an aldehyde group can be achieved under conditions that prevent side reactions such as over- oxidation and undesired removal of the R₃ and R₄ groups. Examples of reagents and reactions that can be used in step A are periodinane reagents, in particular Dess-Martin periodinane (DMP), pyridinium chlorochromate (PCC) and Swern oxidation ((COCl)2/DMSO). In a particular embodiment, step A is carried out using DMP in dichloromethane at room temperature. With “room temperature” should be understood a temperature comprised from 15 to 30 °C. The aldehyde VI obtained after step A can be purified, for example using column chromatography, or can be used in step B as a crude product. Starting material V can be obtained using literature procedures (Oger C. et al., Chem. Eur. J., 2010, 16, p.13976). A typical synthesis is shown in Figure 1. Step B - olefination The transformation of the aldehyde group into an olefin can be achieved by reactions allowing for the formation of the olefin with a selectivity for the Z configuration. Selectivity for the Z-isomer can in particular be achieved by a Wittig reaction, in which the aldehyde is reacted with a phosphorous ylid, which is in turn formed by deprotonation, using a base, of a phosphonium salt. In particular, a suitable phosphonium salt is deprotonated with NaHMDS in dry THF at temperatures below -50 °C, in particular at -78 °C, after which the compound of Formula VI is added. Step C - deprotection The deprotection of the hydroxyl groups, i.e. the removal of the R3 protecting groups can be achieved under conditions depending on the nature of the protecting group. In particular, when R3 is a silyl protecting group, such as a tert-butyldimethyl silyl protecting group, reagents based in fluoride can be used, such as tetrabutylammonium fluoride (TBAF). The deprotection of the hydroxyl groups can, during reaction or purification, lead to the formation of a lactone side product (VII-lactone), formed by an intramolecular transesterification reaction. This lactone can also be hydrolyzed in step D to give the compound of Formula I. Step D - hydrolysis Hydrolysis of the ester function (and/or the lactone group) to obtain a carboxylic acid can be achieved for example using a base such as NaOH, KOH or LiOH, in particular LiOH. Intermediate products, and the compound of Formula I, can be purified using techniques such as column chromatography. Intermediate products, and the compound of Formula I, can be characterized using techniques known to the person skilled in the art, such as NMR, elemental analysis, and mass spectrometry. Purities can be determined using, for example, by using HPLC and chiral HPLC. In a particular embodiment, the starting material V can be used as a mixture of isomers, wherein the configuration of the carbon atom in position 4 is a mixture of R and S. In another particular embodiment, the starting material V can be used as a single isomer, wherein the configuration of the carbon atom in position 4 is R or S. Thus, a seventh object of the present invention relates to a process of preparing a novel compound of Formula IA, wherein the process is as defined above for the compound of Formula I. Despite the structural complexity of the compounds disclosed herein, the inventors were able, after considerable research, to develop a short efficient synthesis for obtaining these compounds. In addition, the inventors have surprisingly found that these compounds are biologically active with respect to diseases related to RyR disfunction. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention. FIGURES: Figure 1: Ca²⁺-sparks frequency recorded in saponin skinned EDL muscle fibres from control (n=5), post myocardial (PMI, n=3) and post myocardial incubated with 4F4t-NeuroP 1μM (PMI + 4F_4t-NeuroP, n=3) mice. *, p<0,05. Figure 2: A.4F_4t-NeuroP prevents diaphragm weakness induced after 6h of mechanical ventilation in anesthetized mice. Force-frequency relationships in diaphragm in control conditions (n=8) or after 6 h of mechanical ventilation with (n=6) or without iv injection of 4F_4t-NeuroP (n=6). Mean maximal force production recorded at 120Hz in control diaphragm, after 6h mechanical ventilation (VIDD) and VIDD treated with 4F4t-NeuroP. Data expressed as mean±SEM, *, p<0,05. B. Dose response relationship of the protective effect of 4F4t-NeuroP, after 6 hours of mechanical ventilation. Mice were treated at the induction of anaesthesia by an IV injection of 4F_4t-NeuroP at a concentration ranging between 0.01 and 100µM. Each value corresponds to the maximal force developed by the diaphragm at the frequency of 120 Hz. C/ Biochemical remodeling of RyR1 after VIDD: impact of 4F_4t-NeuroP. Mean values of DNP/RyR1, P-RyR1/RyR1 and Calstabin1/RyR1 reflecting respectively RyR1 oxidation, phosphorylation on ser2844 and calstabin1 interaction. VIDD affect negatively all parameters and this post-translational remodeling was prevented by 4F4t-NeuroP treatment. Figure 3: A. Force frequency relationship of mice diaphragm muscle, after 12 hours of mechanical ventilation, treated or not with 10µM 4F4t-NeuroP. Moreover, 10µM of 4F4t- NeuroP prevents diaphragm muscle fibres atrophy after 12 hours of mechanical ventilation independently of the fibre phenotype. Representative immunostaining of fast and slow diaphragm muscle fibers in mouse. Antibodies against fast- and slow-type myosin ATPase were used to perform immunostaining on cryosections of mouse diaphragm. Muscle membrane was counterstained with dystrophin antibodies. The staining was performed in diaphragm muscle 12h after MV with or without 4F_4t-NeuroP. Average cross-section area was quantified in each condition including all fibre type (B.) or by discriminating slow versus fast fibres (C.). D. Average distribution of Fast versus Slow twitch fibres in each condition. (* p<0.05 vs control) Figure 4: VB558, a shorter derivative of 4F4t-NeuroP prevents VIDD. A. Structure and synthesis of comparison of VB558. B. Effects of VB558 on the force-frequency relationship in mice ventilated during 6h. (Control n=2; MV n=3; VB5581µM n=6; VB558 10µM n=6 ; * p<0.05 vs MV) Figure 5: VB558 prevents VIDD in piglets after 72 hours of ventilation. Protocol of IV injection of VB558 or methanol (placebo). A. Evolution of the plasmatic concentration of VB558 after a bolus injection in 3 piglets. B. Protocol of IV injection during the 72 hours of mechanical ventilation. The trans-diaphragmatic pressure was measured at different stimulation frequencies of the phrenic nerve, at the beginning of the anaesthesia (t0) and after 72 hours of mechanical ventilation and before (S), in VB558 treated animal (D, n=6) and in placebo group receiving the same volume of solvent (methanol, V) (C, n=6). *p<0,05, **p<0,01, ***p<0,001, ****p<0,0001, t72 vs t0). Figure 6: Effect of Hexanor on the diastolic level of Calcium in ventricular cardiomyocytes derived from DMD and control hIPSc. The cardiomyocytes were loaded with indo-1 to assess in a ratiometric manner the intracellular level of calcium. As demonstrated previously, an elevation of diastolic calcium reflects a RyR2 leaky behavior. A. The level of calcium is higher in DMD compared to control cells. This is prevented by hexanor (1µM). Panel B. The experiments were repeated under isoproterenol stimulation on the cells (Iso 1 µM) showing a full normalization of the resting calcium in this condition. Figure 7 represents a graph showing changes in intercellular calcium transients and changes in peaks of cell contraction as analyzed in example 7. The introduction of 10 nM Iso (isoproterenol) promotes the development of ESV (extrasystole ventricular contraction). Figure 8 represents a graph showing the amount of ryanodine dependant arrhythmic cells in the presence of 10 nM, 100 nM or 1 µM of compound 20,21,22-trinor-4(RS)-4-F4t- NeuroP (compound of Formula III, VB574), as measured in example 7. The amounts of cells are represented as a percentage of total cells, and a control (no VB574) is included. Figure 9 represents a graph showing the amount of ryanodine dependant arrhythmic cells in the presence of 1 µM of monohydroxylated derivative of 4-F_4t-NeuroP (compound of Formula IV), as measured in example 7. The amounts of cells are represented as a percentage of total cells, and a control (no compound of Formula IV) is included. EXAMPLES: Materials & Methods All reactions requiring anhydrous conditions were conducted in dry glassware (oven 120 °C or flame-dried) with magnetic stirring under an atmosphere of nitrogen unless otherwise mentioned. All anhydrous solvents and reagents were dried following standard methods under a nitrogen or argon atmosphere or used as obtained from suppliers (Aldrich, Thermo Fischer). Reactions were monitored by TLC using plates precoated with silica gel 60 with fluorescent indicator 254 nm (Merck). Reaction components were visualized using a 254 nm UV lamp or treatment with acidic p-anisaldehyde stain followed by gentle heating. Column chromatography was performed using silica gel 40–63 μm 230–400 Mesh, Macherey-Nagel or spherical silica gel Si60, 30 µm, Interchim. Pentane (P), Et₂O, EtOAc, MeOH were used for chromatographic separations. Optical rotations were recorded on JASCO P2000-series apparatus and the concentrations c for the optical rotation data are given in g/100mL. Infrared spectra were taken on a Spectrum one (Perkin Elmer) as neat samples using an ATR device and absorptions are given in wave numbers (cm^–1). MS (ESI) and high-resolution MS (HRMS) spectra were measured on a Q-Tof micro spectrometer (resolution 100000, Waters) or on mass spectrometers Synapt G2-S (Waters). Data were obtained by positive or negative electrospray ionization methods between 100 and 1500 Da by direct introduction. NMR spectra were recorded on Bruker AMX300 or Bruker Avance 500 MHz spectrometers in CDCl3 or CD3OD. 1H NMR chemical shifts were provided in ppm using internal reference at δ = 7.26 ppm for CDCl3 and δ = 3.31 ppm for CD₃OD, and are reported as follow: chemical shift in ppm [multiplicity, coupling constant(s) J in Hz, relative integral, attribution]. The multiplicities are defined as follow: br = broad, m = multiplet, s = singlet, d = doublet, t = triplet, q = quadruplet, quint = quintuplet or combinations thereof. ¹³C NMR chemical shifts were referenced against the residual solvent central peak (δ = 77.16 ppm for CDCl₃ and δ = 49.0 ppm for CD₃OD. The connectivity was determined by ¹H-¹H COSY experiments; carbons were assigned according to HSQC and HMBC NMR experiments. Murine model of Heart failure Seven weeks-old male C57Bl/6 mice (Janvier, France) were subjected to a post myocardial infarction after left coronary artery ligation (PMI mice). Briefly, a left thoracotomy was performed under anesthesia and cardiac monitoring (2% isoflurane/O2, Aerrane®, Baxter, France). The artery was ligated 1-2 mm beyond the emergence from the top of the left atrium, using an 8-0 suture. A subcutaneous injection of 0.01 ml buprenorphine solution (0.3 mg.ml^-1) for post-operative analgesia was administered. An echocardiography was systematically realized before the inclusion of animal to ensure that ligation was correctly performed. Only animals surviving at day -5 post-surgery and with comparable echocardiography parameters at this time were included in the study to limit bias due to differences in size infract. All procedures conformed to European Parliament Directive 2010/63/EU and the 22 September 2010 Council on the protection of animals, and were approved by the institutional animal research committee (Departmental Directorate of protecting populations and animal health (ethics for animal welfare and environmental protection, N° A 34 -485) and by our Ethics committee for animal experiments, Languedoc Roussillon, N° CE -LR-0714). 10 to 12 weeks after ligation, mice were euthanized by cervical dislocation and the EDL muscle dissected for calcium sparks recording. Calcium sparks measurements. Diaphragm muscles samples were dissected and stored in a HEPES buffered physiological medium (in mM: 119 NaCl, 5 KCl, 1.25 CaCl2, 1 MgSO4, 10 glucose, 1.1 mannitol, 10 HEPES, pH 7.4). Muscles were then rapidly placed in a dissecting chamber and the solution exchanged with a relaxing solution (in mM: 140 K-glutamate, 10 HEPES, 10 MgCl2, 0.1 EGTA, pH 7.0). Bundles of 5 to 10 EDL fibers were manually dissected, mounted and permeabilized in a relaxing solution containing 0.01% saponin for 30 s. After washing with saponin free solution, the solution was changed to an internal medium for imaging: (in mM) 140 K-glutamate, 5 Na₂ATP, 10 glucose, 10 HEPES, 4.4 MgCl₂, 1.1 EGTA, 0.3 CaCl₂, Fluo-4 0.05 pentapotassium salt (Invitrogen), pH 7.0, for sparks acquisition. Potential sparks were empirically identified using an autodetection algorithm. The mean fluorescence (F0) value for the image was calculated by summing and averaging the temporal F at each spatial location, while ignoring potential spark areas. This F0 value was then used to create a smoothing routine, potential spark locations were visualized and analyzed for spatiotemporal properties. Image analysis was performed using IDL (v5.5, Research System, Inc.). Statistical comparisons were performed using an ANOVA test with a significance level set at P<0.05 (Graphpad Prism v8.4). Murine model of VIDD 35 adult male mice (10 to 12 weeks old, 25 to 30g) C57/BL6 mice were separated into five groups. Three groups were intubated with a 22-gauge angio- catheter and mechanically ventilated for 6 consecutive hours using a volume-driven small-animal ventilator (Minivent®, Harvard Apparatus, Saint-Laurent, Canada). Tidal volume was established at 10µl/mg body weight with a respiratory rate of 150 breaths/min, a positive end-expiratory pressure (PEEP) level from 2 to 4 cm H₂O and a fraction of inspired oxygen of 0.21. Non-spontaneous ventilation was defined as a lack of diaphragm contractile activity attested by repetitive stereotypical deflections observed in the airway pressure curve. The mice were divided into two groups. The first group (control) received methanol, at the volume corresponding to the equivalent volume brought with 4F_4t-NeuroP, intravenously (IV) infused over a 5-minute period, 20 minutes before start of MV. The second group of mice received 4F4t-NeuroP intravenously (IV) infused over a 5-minute period, 20 minutes before start of MV. The two groups were intubated and treated in an identical manner (see Matecki et al., 2016 for details¹⁵). Contractile function in murine muscle samples At the end of the protocol of MV, the entire diaphragm was surgically excised and mice were euthanized, by exsanguination. Isometric contractile properties were assessed as described previously in detail (Matecki et al., 2016¹⁵). The excised diaphragm strip was mounted into jacketed tissue bath chambers filled with equilibrated and oxygenated Krebs solution. The muscles were supra-maximally stimulated using square wave pulses (Model S48; Grass Instruments, West Warwick, RI). The force–frequency relationship was determined by sequentially stimulating the muscles for 600 ms at 10, 20, 30, 50, 60, 80, 100 and 120Hz with 1 minute between each stimulation train. After measurement of contractile properties, muscles were measured at Lo (the length at which the muscle produced maximal isometric tension), dried and weighted. For comparative purposes, diaphragmatic force production was normalized for total muscle strip cross-sectional area and expressed in N.cm^-2. The total muscle strip cross- sectional area was determined by dividing muscle weight by its length and tissue density (1.056 g/cm³). The rest of the diaphragm was partitioned, one part was quick frozen in liquid nitrogen and secondarily used for biochemical analysis, and the other part was used freshly for Ca²⁺ spark measurements. RyR1 biochemical analysis Muscle biopsies were homogenized in 150 µl of buffer containing 5% SDS, 5% beta- mercaptoethanol, 10% glycerol, 10 mM EDTA and 50 mM Tris/HCl buffer (pH= 8.0). Each sample was immediately denatured at 90°C for 4 min. After centrifugation (5000 rpm) at 4°C, supernatant protein concentrations were measured in duplicate using the BCA protein assay, equilibrated at the same concentration by dilution with loading buffer and aliquoted at 2 µg/µl. RyR1 was immunoprecipitated from 250 µg of homogenate using an anti-RyR antibody (4 µg RyR1-1327) in 0.5 ml of a modified RIPA buffer (50 mM Tris-HCl pH 7.4, 0.9% NaCl, 5.0 mM NaF, 1.0 mM Na₃VO₄, 1% Triton-X100, and protease inhibitors) for 1 hr at 4°C. The immune complexes were incubated with protein A Sepharose beads (Amersham Pharmacia) at 4°C for 1 hr and the beads were washed three times with buffer. Proteins were separated on SDS-PAGE gels (4-20% gradient) and transferred onto nitrocellulose membranes for 2 hr at 200 mA (SemiDry transfer blot, Bio-Rad). To prevent non-specific antibody binding, the membranes were incubated with blocking solution (LICOR Biosciences) and washed with Tris- buffered saline with 0.1% Tween-20. Blots were respectively incubated with primary antibody to RyR1 (RyR1-1327, an affinity-purified rabbit polyclonal antibody raised against a KLH-conjugated peptide with the amino acid sequence CAEPDTDYENLRRS, corresponding to residues 1327–1339 of mouse skeletal RyR1, with an additional cysteine residue added to the amino terminus), and affinity purified with the unconjugated peptide. The inventors also used antibody to calstabin1 (1: 2500 in blocking buffer, LICOR Biosciences); phospho-epitope–specific antibody to human RyR2 phosphorylated on Ser-2808 (1:5,000), which detects PKA-phosphorylated mouse RyR1 (on Ser-2844) and RyR2 (on Ser-2808); antibody to S-nitrosylated cysteine residues (1:1000, Sigma). To determine RyR1 oxidation, the immunoprecipitate was treated with 2, 4- dinitrophenyl hydrazine, and the derivatized carbonyls were detected using an OxyBlot protein oxidation detection Kit (catalog S7150, Chemicon International Inc.). After three washes, membranes were incubated with infrared-labeled secondary antibodies. Control samples were analyzed on each gel for normalization and total levels of RyR1 were not different between groups. Piglet model As previously described^18,25, twelve piglets (15–20 kg) were separated in two groups of six animals/each. In both groups, oxygenation was maintained with a fraction of inspired oxygen (FIO2) ranging from 25 to 35%, tidal volume between 10 and 12ml.kg^-1 body weight and breathing frequency from 15 to 30 cycles/min to maintain normocapnia. In the first group (MV group), piglets were mechanically ventilated using CMV, with a positive end-expiratory pressure level at 5 cm H₂O. The absence of spontaneous breathing was verified on the ventilator trend graphs, and the diaphragm electromyographic activity was measured to ensure the absence of diaphragm electrical activity. In the second group (control group), piglets were ventilated using ASV, with settings in phase with the piglet body weight (inspiratory flow trigger at 0.3L.min^-1, percentage of mechanical ventilation between 100 and 150%, positive end-expiratory pressure level at 5cm H2O, and expiratory trigger at 25% of the peak inspiratory flow). The diaphragm electromyographic activity was assessed to verify that piglets could breathe spontaneously. Both groups received the same care, except for the MV mode. Briefly, piglets were anesthetized by intravenous injection of 5–6 mg kg^-1 pentobarbital sodium, intubated with a cuffed endotracheal tube and mechanically ventilated (Galileo®; Hamilton Medical AG, Rhazuns, Switzerland). Anesthesia was maintained with continuous intravenous infusion of 15-20mg.kg^-1 propofol, 0.1-0.3mg.kg^-1 midazolam and 3-4mg.kg^-1.h^-1 ketamine. The level of sedation was monitored by using a bispectral index system (BIS®; Aspect, Norwood, MA). Heating pads were employed, as needed, to maintain the normal body temperature of 38.5-39.5°C. A carotidal arterial catheter (PiCCO®; Pulsion, Munich, Germany) was inserted for monitoring the heart rate, arterial blood pressure and cardiac output. The absence of spontaneous breathing in the MV group was verified using the ventilator trend graphs and the diaphragm electromyographic activity measurement. Arterial carbon dioxide pressure was monitored using a capnograph (Deltatrac®; Datex- Ohmeda, Helsinki, Fin- land) and verified by arterial blood gas analysis (iSTAT®; Abbott, Abbott Park, IL). Parenteral nutrition was given from the first day (10% glucose, 20% amino acids solution and Hyperamine 20®; Braun, Boulogne Billancourt, France) to provide 30- 35kcal.kg^-1.day^-1. All procedures were performed aseptically. All animals received prophy- lactic intravenous injections of antibiotics three times per day (100 mg.kg^-1.day^-1amoxicillin– clavulanate). The diaphragm contractile function was assessed in vivo by measuring the transdiaphragmatic pressure (Pdi)¹⁸. A double-lumen air-filled balloon-tipped catheter was placed transorally in the stomach and the distal third of the esophagus. Bipolar transvenous pacing catheters were introduced through each internal jugular vein and adjusted to stimulate the phrenic nerve and subsequently induce the diaphragm contraction by supramaximal stimulation at frequencies ranging from 20 to 120 Hz with trains of stimulation of 2s and 150ms. Experimental and placebo solutions were IV injected just before intubation of the animal at a concentration of 0.250mg.kg^-1 followed by a maintenance dose of 0.025mg.kg^-1 every twelve hours. For these experiments, the surgeons working on the piglets did not know what was injected, placebo or VB558. The analysis was performed blindly by a third person and the belonging of the piglets unraveled after. Statistics Three kinds of statistical analysis were performed, 1/ independent student t-tests when comparing a given parameter (cross-section area, % of fibers) in two conditions (following or not mechanical ventilation) 2/ one-way ANOVA followed by the post-hoc Tukey test when comparing a given parameter (sparks, maximal diaphragmatic force at 120Hz, ratio of co- immunoprecipitation) in three conditions (control, VIDD, VIDD+VB558) 3/ two-way repeated measures ANOVA followed by the post-hoc Bonferoni test when comparing force or Pdi- frequencies relationships. SYNTHESIS Example 1 synthesis of compound II - [17,18,19,20,21,22]-hexanor-4F4tNeuroprostane - (VB558) Compound II was prepared according to Scheme 1: Scheme 1: a) DMP, CH2Cl2, RT; b) BrPh3P(CH2)2CH3, NaHMDS, THF, -78°C to RT, 81% 2 steps; c) TBAF, THF, RT, 40%; d) LiOH, THF/H₂O (1:1), RT, 36%. Example 1a synthesis of (E)-methyl 6-((1S,2R,3R,5S)-3,5-bis((tert-butyldimethylsilyl)oxy)- 2-((Z)-pent-2-en-1-yl)cyclopentyl)-4-((tert-butyldimethylsilyl)oxy)hex-5-enoate 2 To a solution of the alcohol 1 (390 mg, 0.62 mmol, 1eq) in DCM (10 mL) was added at RT DMP (2.43 mL, 0.38M in DCM, 0.93 mmol, 1.5eq). After 30 minutes stirring at RT, the reaction was quenched by addition of a 10% Na2S2O3/NaHCO3 (1:1, v/v) aqueous solution (about 10 mL). The organic phase was separated, the aqueous phase was extracted with Et₂O (3 x 10 mL). The combined organic phases were washed with a 10% Na2S2O3/NaHCO3 (1:1, v/v) aqueous solution (ca. 10 mL), then brine, dried over MgSO4 and concentrated under vacuum. The crude product was used in the next step of the synthesis. To a solution of propyltriphenylphosphonium bromide (550 mg, 1.42 mmol, 2.3eq) in dry THF was added at RT NaHMDS (682 mL, 2M in THF, 1.36 mmol, 2.2eq) and the mixture was stirred 1h at RT. The reaction was cooled to -78°C and added via a cannula to a solution of the aldehyde (390 mg, 0.62 mmol, 1eq) in dry THF (4 mL). The reaction was raised to RT overnight and quenched with a 10% NH4Cl aqueous solution (ca. 10 mL), extracted with Et2O (3 x 10 mL) and the combined organic phases were washed with a 10% NH₄Cl aqueous solution (ca. 20 mL), with brine, dried over MgSO4 and concentrated under vacuum. The crude extract was purified by SiO2 column chromatography (pentane/Et2O 95:5) to afford 2 (260 mg, 81% over 2 steps) as a colorless oil. R_f=0.66 (pentane/Et₂O 95:5). ¹H NMR (300 MHz, CDCl₃) δ 5.48 – 5.24 (m, 4H), 4.15 – 4.13 (m, 1H), 3.96 – 3.70 (m, 2H), 3.64 (s, 3H), 2.68 – 2.48 (m, 1H), 2.41 – 2.22 (m, 3H), 2.16 – 1.38 (m, 8H), 0.94 (t, J = 7.5, 3H), 0.91 – 0.80 (s, 27H), 0.00 (s, 18H). ¹³C NMR (75 MHz, CDCl₃) δ 174.40, 134.94 dia 1, 134.86 dia 2, 132.31 dia1, 132.21 dia 2, 129.37 dia 1, 128.90 dia 2, 127.92, 76.30, 76.08, 72.21 dia 1, 72.05 dia 2, 52.60 dia 152.46 dia 2, 51.64, 50.35 dia 1, 50.21 dia 2, 33.32, 29.73, 26.01, 20.82, 18.20, 14.41, -4.20, -4.41, -4.58. Example 1b synthesis of (E)-methyl 6-((1S,2R,3R,5S)-3,5-dihydroxy-2-((Z)-pent-2-en-1- yl)cyclopentyl)-4-hydroxyhex-5-enoate 3 To compound 2 (260 mg, 0.4 mmol, 1eq), was added TBAF (4.76 mL, 1M in THF, 4.76 mmol, 12eq). After 1h stirring at RT, the reaction was quenched by adding DOWEX-50W resin (2.5 g), CaCO3 (2.5g) and MeOH (75 mL), stirred 1h at RT, filtered over a pad of Celite^® and concentrated under vacuum. The crude was purified by SiO2 column chromatography (100% EtOAc) to afford 3 as a mixture of ester/lactone in a ratio of 72:28 (50 mg, 40%) as a colorless oil. R_f=0.30 (100% EtOAc). Ester: ¹H NMR (300 MHz, CDCl₃) δ 5.65 – 5.23 (m, 4H), 4.15 – 3.85 (m, 3H), 3.64 (s, 3H), 2.75 (dt, J = 14.0, 7.4 Hz, 2H), 2.58 – 2.28 (m, 4H), 2.11 – 1.96 (m, 3H), 1.96 – 1.94 (m, 1H), 1.94 – 1.82 (m, 2H), 1.82 – 1.75 (m, 1H), 1.65 – 1.52 (m, 1H), 1.13 (s, 1H), 0.92 (t, J = 7.5 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.47, 135.18, 133.12, 130.42, 127.22, 76.19, 76.07, 75.97, 72.05, 53.26, 51.78, 50.87, 42.32, 42.14, 31.94, 30.15, 28.79, 28.56, 26.69, 20.73, 14.24. Lactone: ¹ H NMR (300MHz, CDCl3): 5.61-5.55 (m, 2H), 5.44-5.24 (m, 2H), 4.92-4.86 (m, 1H), 4.12- 3.92 (m, 4H), 2.83-2.79 (m, 1H), 2.53-2.30 (m, 5H), 2.18-2.15 (m, 1H), 2.00-1.93 (m, 4H), 1.67-1.60 (m, 1H), 0.93 (s, 3H). Example 1c Synthesis of (E)-6-((1S,2R,3R,5S)-3,5-dihydroxy-2-((Z)-pent-2-en-1- yl)cyclopentyl)-4-hydroxyhex-5-enoic acid II To a solution of 2 (50mg, 0.18mmol, 1eq) in 4 mL THF/H2O (1:1, v/v) was added LiOH (45 mg, 1.07 mmol, 6eq) at RT. After stirring for 1h15, the reaction was quenched by a solution of 1M NaHSO₄ until acidic pH, extracted with EtOAc (10mL), washed with brine, dried over MgSO₄ and concentrated under vacuum. The crude product was purified by SiO₂ column chromatography (100% EtOAc) to afford compound II (27 mg, 36%) as a colorless oil. R_f=0.13 (100% EtOAc). ¹H NMR (300 MHz, MeOD) δ 5.60 – 5.47 (m, 2H), 5.42 – 5.31 (m, 2H), 4.16 – 4.02 (m, 1H), 4.00 – 3.92 (m, 1H), 3.85 (dt, J = 7.0, 5.0 Hz, 1H), 2.67 (s, 1H), 2.46 (dt, J = 14.6, 7.4 Hz, 1H), 2.35 (dd, J = 8.2, 7.0 Hz, 2H), 2.15 – 1.93 (m, 5H), 1.76 (td, J = 7.7, 6.6 Hz, 2H), 1.51 (dt, J = 14.2, 5.0 Hz, 1H),0.94 (t, J = 7.5 Hz, 3H). ¹³C NMR (75 MHz, MeOD) δ 176.04, 134.62, 131.93, 129.12, 127.31, 127.16, 74.81, 74.72, 71.07, 52.10, 50.03, 42.17, 32.02, 29.66, 25.76, 20.26, 13.27. ESI-: 297.17 [M-H]-. HRMS (ESI-) calculated for C₁₆H₂₅O₅ [M-H]- 297.1702, found 297.1707. Example 2 synthesis of compound III - 20,21,22-trinor-4(RS)-4-F4t-NeuroP - (VB574) Compound III was prepared according to Scheme 2: Scheme 2 : a) DMP, CH2Cl2, RT; b) (Z)-hex-3-en-1-yltriphenylphosphonium iodide, NaHMDS, THF, -78°C to RT, 83% 2 steps; c) TBAF, THF, RT, 59%; d) LiOH, THF/H2O (1:1), RT, 69%. Example 2a Synthesis of (E)-methyl 6-((1S,2R,3R,5S)-3,5-bis((tert- butyldimethylsilyl)oxy)-2-((2Z,5Z)-octa-2,5-dien-1-yl)cyclopentyl)-4-((tert- butyldimethylsilyl)oxy)hex-5-enoate 5 To a solution of the alcohol 4 (467 mg, 0.74 mmol, 1 eq) in DCM (10 mL) was added at RT DMP (2.31 mL, 0.38M in DCM, 1.11 mmol, 1.5eq). After 30 min stirring at RT, the reaction was quenched by addition of a 10% Na₂S₂O₃/NaHCO₃ (1:1, v/v) aqueous solution (ca.10 mL). The organic phase was separated, the aqueous phase was extracted with Et₂O (3 x 10 mL) and the combined organic phases were washed with a 10% Na2S2O3/NaHCO3 (1:1, v/v) aqueous solution (ca. 10 mL), then with brine, dried over MgSO4 and concentrated under vacuum. The crude product was used in the next step of the synthesis. To a solution of (Z)-hex-3-en-1-yltriphenylphosphonium iodide (803 mg, 1.7 mmol, 2.3eq) in dry THF was added at RT NaHMDS (815 µL, 2M in THF, 1.63 mmol, 2.2eq) and the mixture was stirred 0.5h at -50°C. The reaction was cooled to -78°C and added via a cannula to a solution of the aldehyde (465 mg, 0.74 mmol, 1eq) in dry THF (5 mL) and stirred 3h and quenched with a 10% NH4Cl aqueous solution (ca. 10 mL), extracted with Et2O (3 x 10 mL) and the combined organic phases were washed with a 10% NH₄Cl aqueous solution (ca. 20 mL), with brine and dried over MgSO₄ and concentrated under vacuum. The crude extract was purified by SiO2 column chromatography (pentane/Et2O 95:5) to afford 5 (172 mg, 83% over 2 steps) as a colorless oil. Rf = 0.60 (pentane/Et2O 95:5). ¹H NMR (300 MHz, CDCl₃) δ 5.57 – 5.16 (m, 6H), 4.14 (m, 1H), 3.98 – 3.74 (m, 2H), 3.63 (s, 3H), 2.66 (m, 3H), 2.42 – 2.19 (m, 3H), 2.17 – 1.62 (m, 7H), 1.51 (dt, J = 13.9, 5.0 Hz, 1H), 0.94 (t, J = 7.5Hz, 3H), 0.89 (s, 27H), 0.00 (s, 18H). ¹³C RMN (100 MHz, CDCl₃): 174.21, 134.87, 131.88, 129.08, 128.60, 128.51, 125.55, 76.15, 75.96, 72.00, 52.32, 51.50, 50.00, 44.36, 33.18, 29.58, 26.05, 25.85, 25.69, 20.58, 18.06, 14.32, -4.57. HRMS (ESI⁺) calculated for C38H74O5Si3[M]⁺ 695.4922, found 695.4918. Example 2b Synthesis of 5-((E)-2-((1S,2R,3R,5S)-3,5-dihydroxy-2-((2Z,5Z)-octa-2,5-dien- 1-yl)cyclopentyl)vinyl)dihydrofuran-2(3H)-one 6 To compound 5 (170 mg, 0.247 mmol, 1eq), was added TBAF (1.48 mL, 1M in THF, 1.48 mmol, 6eq). After 1h stirring at RT, the reaction was quenched by adding DOWEX-50W resin (1.2 g), CaCO3 (0.4g) and MeOH (10 mL), stirred 1h at RT, filtered over a pad of Celite® and concentrated under vacuum. The crude was purified by SiO2 column chromatography (100% EtOAc) to afford 6 (47 mg, 59%) as a colorless oil. Rf=0.38 (100% EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 5.61 (dt, J = 5.0, 1.8 Hz, 2H), 5.45 – 5.18 (m, 4H), 4.89 (td, J = 7.4, 3.2 Hz, 1H), 4.00 (m, 2H), 2.77 (m, 3H), 2.59 – 2.29 (m, 4H), 2.26 – 1.87 (m, 6H), 1.65 (dd, J = 10.5, 4.2 Hz, 1H), 0.95 (t, 3H). ¹³C RMN (100 MHz, CDCl₃): 177.09, 132.69, 132.39, 130.22, 129.81, 127.97, 126.74, 80.47, 76.29, 53.37, 50.85, 42.36, 28.82, 28.58, 26.85, 25.72, 20.63, 14.31. HRMS (ESI⁺) calculated for C₁₉H₂₉O₄ [M+H]⁺ 321.2066, found 321.2068. Example 2c Synthesis of (E)-6-((1S,2R,3R,5S)-3,5-dihydroxy-2-((2Z,5Z)-octa-2,5-dien-1- yl)cyclopentyl)-4-hydroxyhex-5-enoic acid III To a solution of 6 (47mg, v/v) was added LiOH (37 mg, 0.88 mmol, 6eq) at RT. After 1h15 stirring, the reaction was quenched by a solution of 1M NaHSO₄ until acidic pH, extracted with EtOAc (10mL), washed with brine, dried over MgSO₄ and concentrated under vacuum. The crude product was purified by SiO₂ column chromatography (100% EtOAc) to afford compound III (34 mg, 69%) as a colorless oil. R_f=0.13 (100% EtOAc). ¹H MHz, CD3OD) δ 5.58 – 5.47 (m, 2H), 5.43 – 5.20 (m, 4H), 4.11 – 4.01 (m, , = 7.3, 4.9 Hz, 1H), 3.85 (dt, J = 7.7, 5.0 Hz, 1H), 2.82 – 2.65 (m, 3H), 2.45 (dt, J = 14.5, 7.4 Hz, 1H), 2.34 (td, J = 7.5, 2.1 Hz, 2H), 2.16 – 1.96 (m, 5H), 1.83 – 1.70 (m, 2H), 1.52 (dt, J = 14.2, 5.1 Hz, 1H), 0.94 (t, J = 7.6 Hz, 3H). ¹³C RMN (100 MHz, CDCl3): 179.93, 136.15, 134.35, 132.76, 131.49, 130.45, 128.32, 82.82, 76.19, 75.93, 53.41, 51.41, 43.57, 33.45, 29.71, 27.31, 26.62, 21.49, 14.69. HRMS (ESI-) calculated for C19H30O5 [M-H]- 337.2015, found 337.2007. Example 3 Synthesis of α-chain synthon for the monohydroxylated derivative IV Silyl protected intermediate 11 was prepared according to the reaction Scheme 3: Scheme 3: α-chain synthon 11 of the monohydroxylated derivative IV Example 3a Synthesis of (E)-methyl 6-((1R,2R,5S)-2-(2-acetoxyethyl)-5-((tert- butyldimethylsilyl)oxy)cyclopentyl)-4-oxohex-5-enoate 8 To a solution of the alcohol 7 (1g, 3.16 mmol, 1eq) in DCM (30 mL) was added at RT DMP (12.5 mL, 0.38M in DCM, 4.74 mmol, 1.5eq). After 30 minutes stirring at RT, the reaction was quenched by addition of a 10% Na₂S₂O₃/NaHCO₃ (1:1, v/v) aqueous solution (ca.20 mL). The organic phase was separated, the aqueous phase was extracted with Et₂O (3 x 200 mL) and the combined organic phases were washed with a 10% Na2S2O3/NaHCO3 (1:1, v/v) aqueous solution (ca. 20 mL) and with brine, dried over MgSO4 and concentrated under vacuum. The crude product was used in the next step of the synthesis. To a solution of methyl 5-(dimethoxyphosphoryl)-4-oxopentanoate (3.1g, 13 mmol, 3.4eq) in dry THF was added at 0°C NaHMDS (6mL, 2M in THF, 12.16 mmol, 3.2eq) and the mixture was stirred 1h at 0°C. The reaction was cooled to -78°C and added via a cannula to a solution of the aldehyde (1.2g, 3.8 mmol, 1eq) in dry THF (10 mL) and stirred 14h and quenched with brine (ca. 20 mL), extracted with Et₂O (3 x 20 mL) and the combined organic phases were washed with brine and dried over MgSO₄ and concentrated under vacuum. The crude extract was purified by SiO2 column chromatography (pentane/Et2O 9:1) to afford 8 (1.3g, 80% over 2 steps) as a colorless oil. Rf = 0.64 (pentane/Et2O 9:1). ¹H NMR (300 MHz, CDCl₃) δ 6.53 (dd, J = 15.7, 10.3 Hz, 1H), 6.08 (d, J = 15.7 Hz, 1H), 4.01 – 3.85 (m, 3H), 3.59 (s, 3H), 2.78 (t, J = 6.7 Hz, 2H), 2.58 – 2.44 (m, 3H), 2.31 (q, J = 8.1 Hz, 1H), 1.93 (s, 5H), 1.66 – 1.33 (m, 3H), 1.33 – 1.16 (m, 1H), 0.77 (s, 9H), -0.07 (d, J = 1.2 Hz, 6H). Example 3b Synthesis of (E)-methyl 6-((1R,2R,5S)-2-(2-acetoxyethyl)-5-((tert- butyldimethylsilyl)oxy)cyclopentyl)-4-hydroxyhex-5-enoate 9 To a solution of the enone 8 (1.2g, 2.8 mmol, 1.0 eq) in 30 mL of dry MeOH, was added CeCl3 (1.04g, 2.8 mmol, 1.0 eq). After 15 mn, the mixture is cooled to 0°C and NaBH4 (53 mg, 1.4 mmol, 0.5 eq). is added. After 20 mn the reaction is completed, 30mL of EtOAc and 30 mL of brine are added. The aqueous phase was extracted with 3 x 20 mL of EtOAc. The organic layer was extracted with 20 mL of brine, dried over MgSO4, filtered and the solvents removed under reduced pressure. The alcohol 9 was obtained and used directly into reaction without further purification (1.15g, 96%). Rf = 0.35 (pentane/Et2O 1:1). ¹H NMR (300 MHz, CDCl₃) δ 5.56 – 5.42 (m, 1H), 5.42 – 5.22 (m, 1H), 4.18 – 3.80 (m, 4H), 3.62 (s, 3H), 2.43 – 2.30 (m, 3H), 2.22 (dt, J = 17.0, 7.5 Hz, 1H), 1.97 (dd, J = 3.5, 1.9 Hz, 5H), 1.85 – 1.69 (m, 3H), 1.64 – 1.40 (m, 3H), 1.20 (td, J = 7.2, 3.7 Hz, 1H), 0.81 (s, 9H), -0.03 (d, J = 1.0 Hz, 6H). Example 3c Synthesis of (E)-methyl 6-((1R,2R,5S)-2-(2-acetoxyethyl)-5-((tert- butyldimethylsilyl)oxy)cyclopentyl)-4-((tert-butyldimethylsilyl)oxy)hex-5-enoate 10 To a solution of the alcohol 9 (1.1g, 2.6 mmol, 1.0 eq) in 100 mL of CH₂Cl₂, was added TBSCl (1.2g, 7.7 mmol, 3.0 eq), imidazole (0.7g, 10.3 mmol, 4.0 eq), and 4-DMAP (cat.). After 4.5 hours, the reaction is completed, 100mL of Et2O and 100 mL of brine are added. The aqueous phase was extracted with 3 x 50 mL of Et₂O. The organic layer was extracted with 50 mL of brine, dried over MgSO4 and the solvents removed under reduced pressure. Compound 10 was obtained and used directly into reaction without further purification (1.3 g, quant.). Rf = 0.89 (pentane/Et2O 1:1). ¹H NMR (300 MHz, CDCl₃) δ 5.61 – 5.07 (m, 2H), 3.96 (m, 4H), 3.59 (s, 3H), 2.26 (dd, J = 7.5, 3.6 Hz, 4H), 2.08 – 1.05 (m, 11H), 0.97 – 0.59 (m, 18H), 0.31 – -0.13 (m, 12H). Example 3d Synthesis of (E)-methyl 4-((tert-butyldimethylsilyl)oxy)-6-((1R,2S,5R)-2-((tert- butyldimethylsilyl)oxy)-5-(2-hydroxyethyl)cyclopentyl)hex-5-enoate 11 To a solution of acetate 10 (1.3g, 2.4 mmol, 1eq) in 35 mL of dry MeOH was added dried K2CO3 (1.3g, 9.6 mmol, 4eq) and stirred at RT. After 3 hours, the reaction was quenched by adding 20mL of a solution Et2O/H2O 1:1 and stirred 1 hour. The aqueous phase was extracted with Et₂O (3 x 20 mL), and the organic combined phases washed with brine, dried over MgSO₄ and concentrated under vacuum. The crude extract was purified by SiO2 column chromatography (20 to 50% Et2O/pentane gradient) to afford 11 as follow: 4S-epimer (S)-11 (0.47g, 37%), 4-R/S-epimers mixture (0.15g, 12%), and 4R-epimer (R)-11 (0.28g, 23%). Rf = 0.50 (pentane/Et2O 1:1) 4S-epimer ; Rf = 0.40 (pentane/Et2O 1:1) 4R-epimer (E)-methyl 4S-((tert-butyldimethylsilyl)oxy)-6-((1R,2S,5R)-2-((tert-butyldimethylsilyl)oxy)- 5-(2-hydroxyethyl)cyclopentyl)hex-5-enoate (S)-11 ¹H NMR (300 MHz, CDCl₃) δ 5.46 – 5.20 (m, 2H), 4.11 (d, J = 5.7 Hz, 1H), 3.88 (dt, J = 5.9, 2.7 Hz, 1H), 3.64 – 3.50 (m, 5H), 2.35-2.31 (m, 4H), 1.90-1.04 (m, 8H), 0.82 (m, 18H), 0.07 – -0.44 (m, 12H). ¹³C NMR (125 MHz, CDCl₃) δ 174.32, 134.51, 128.76, 79.32, 71.84, 62.13, 55.10, 51.50, 37.05, 34.75, 33.67, 33.10, 29.53, 26.02, 18.17, -4.41. (E)-methyl 4R-((tert-butyldimethylsilyl)oxy)-6-((1R,2S,5R)-2-((tert-butyldimethylsilyl)oxy)- 5-(2-hydroxyethyl)cyclopentyl)hex-5-enoate (R)-11 ¹H NMR (300 MHz, CDCl3) δ 5.55 – 5.09 (m, 2H), 4.08 (q, J = 6.1 Hz, 1H), 3.95 (dt, J = 5.9, 2.2 Hz, 1H), 3.72 – 3.44 (m, 5H), 2.32 (m, 4H), 2.03 – 1.03 (m, 8H), 0.84 (s, 18H), -0.01 (s, 12H). ¹³C NMR (125 MHz, CDCl3) δ 174.27, 134.84, 128.85, 79.06, 72.34, 62.15, 55.29, 51.60, 36.99, 34.82, 33.63, 33.29, 29.71, 26.04, 18.18, -4.24. Example 4 Synthesis of compound IV Compound IV, both (S)-IV and (R)-IV), was prepared from the synthon obtained in example to Scheme 4: - 4(R)-4-F4t-neuroprostane Example 4a Synthesis of (S,E)-methyl 4-((tert-butyldimethylsilyl)oxy)-6-((1R,2S,5R)-2- ((tert-butyldimethylsilyl)oxy)-5-((2Z,5Z,8Z)-undeca-2,5,8-trien-1-yl)cyclopentyl)hex-5- enoate (S)-12 To a solution of (S)-11 (0.4g, 0.79 mmol, 1eq) in DCM (15 mL) was added DMP (0.5 mg, 1.18 mmol, 1.5eq) and the reaction was allowed to stir at RT. After 30 mn, the reaction was quenched by adding a 10% NaHCO3/Na2S2O3(1/1, v/v) aqueous solution. The aqueous phase was extracted with Et2O (3 x 20 mL), washed with brine, dried over MgSO4 and concentrated under vacuum to afford the crude aldehyde (0.39 g, 99%). Under N2 and at -40°C, to a solution of previously described triphenylphosphonium iodide (0.91g, 1.78 mmol, 2.25 eq) in THF (10 mL) was slowly added NaHMDS (0.83 mL, 1.66 mmol, 2M/THF, 2.1eq). After 1 hour stirring at -40°C, the bright orange ylide was cooled to -78°C, slowly added via a cannula to a solution of the previously prepared crude aldehyde in THF (4 mL) and stirred 1 hour. The mixture was poured onto silica gel and eluted with a gradient of pentane/Et₂O (1:0 to 9:1). The solvents were carefully evaporated at RT and 700 mbar, to afford (S)-12 (126 mg, brsm (based on recovered starting material), 41%, 2 steps) as a colorless oil. R_f = 0.80 (pentane/Et₂O 9:1). MHz, CDCl3) δ 5.66 – 5.01 (m, 8H), 4.13 (q, J = 5.6 Hz, 1H), 3.92 (dd, J = 5.9, , – 3.55 (m, 3H), 2.76 (dd, J = 5.0, 3.3 Hz, 4H), 2.50 – 1.68 (m, 11H), 1.64 – 1.42 (m, 1H), 1.24-1.20 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H), 0.85 (s, 18H), 0.01 (s, 12H). ¹³C NMR (125 MHz, CDCl3) δ 174.41, 134.62, 131.97, 129.48, 129.25, 128.36, 128.20, 128.03, 127.15, 79.07, 72.23, 55.16, 51.46, 41.20, 33.71, 33.23, 29.65, 29.39, 28.50, 25.90, 25.78, 25.64, 20.57, 18.10, 14.29, -4.28. [α]_D ²⁰(MeOH)= +7.86 (c=1.26). Example 4b Synthesis of (R,E)-methyl 4-((tert-butyldimethylsilyl)oxy)-6-((1R,2S,5R)-2- ((tert-butyldimethylsilyl)oxy)-5-((2Z,5Z,8Z)-undeca-2,5,8-trien-1-yl)cyclopentyl)hex-5- enoate (R)-12 To a solution of (R)-11 (0.25g, 0.5 mmol, 1eq) in DCM (10 mL) was added DMP (0.32 g, 0.75 mmol, 1.5eq) and the reaction was allowed to stir at RT. After 30 min, the reaction was quenched by adding a 10% NaHCO₃/Na₂S₂O₃(1/1, v/v) aqueous solution. The aqueous phase was extracted with Et₂O (3 x 20 mL), washed with brine, dried over MgSO₄ and concentrated under vacuum to afford the crude aldehyde (0.244 g, 98%). Under N₂ and at -40°C, to a solution of previously described triphenylphosphonium iodide (0.58g, 1.12 mmol, 2.25 eq) in THF (10 mL) was slowly added NaHMDS (0.5 mL, 1 mmol, 2M/THF, 2.1eq). After 1 hour stirring at -40°C, the bright orange ylide was cooled to -78°C, slowly added via a cannula to a solution of the previously prepared crude aldehyde in THF (4 mL) and stirred 1 hour. The mixture was poured onto silica gel and eluted with a gradient of pentane/Et2O (1:0 to 9:1). The solvents were carefully evaporated at RT and 700 mbar, to afford (R)-12 (66 mg, BRSM 30%, 2 steps) as colorless oil. Rf = 0.84 (pentane/Et2O 9:1). ¹H NMR (300 MHz, CDCl₃) δ 5.64 – 5.16 (m, 8H), 4.12 (q, J = 6.0 Hz, 1H), 3.97 (dd, J = 5.8, 2.8 Hz, 1H), 3.63 (s, 3H), 2.77 (q, J = 5.6, 5.2 Hz, 4H), 2.54 –1.75 (m, 11H), 1.61 – 1.50 (m, 1H), 1.37 – 1.20 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H), 0.86 (s, 18H), 0.01 (s, 12H). ¹³C NMR (125 MHz, CDCl3) δ 174.20, 134.61, 132.05, 129.50, 129.15, 128.56, 128.37, 128.20, 127.20, 78.85, 72.05, 55.21, 51.49, 41.29, 33.75, 33.23, 29.63, 29.24, 28.45, 26.05, 25.65, 25.54, 20.57, 18.19, 14.32, -4.24. [α]D²⁰(MeOH)= +18.2 (c=5). Example 4c Synthesis of (S)-5-((E)-2-((1R,2S,5R)-2-hydroxy-5-((2Z,5Z,8Z)-undeca-2,5,8- trien-1-yl)cyclopentyl)vinyl)dihydrofuran-2(3H)-one (S)-13 To compound (S)-12 (126 mg, 0.2 mmol, 1eq), was added TBAF (0.84 mL, 1M in THF, 0.84 mmol, 4eq). After 2h stirring at RT, the reaction was quenched by adding DOWEX-50W resin (1.2 g), CaCO₃ (0.4g) and MeOH (15 mL), stirred 1h at RT, filtered over a pad of Celite® and concentrated under vacuum. The crude was purified by SiO₂ column chromatography (100% EtOAc) to afford (S)-13 (51 mg, 72%) as a colorless oil, which is a mixture 1:1 of lactone/ester. R_f = 0.34 (EtOAc). Example 4d Synthesis of (R)-5-((E)-2-((1R,2S,5R)-2-hydroxy-5-((2Z,5Z,8Z)-undeca-2,5,8- trien-1-yl)cyclopentyl)vinyl)dihydrofuran-2(3H)-one (R)-13 To compound (R)-12 (60 mg, 0.1 mmol), was added TBAF (0.4 mL, 1M in THF, 0.4 mmol). After 2h stirring at RT, the reaction was quenched by adding DOWEX-50W resin (0.6 g), CaCO₃ (0.2 g) and MeOH (10 mL), stirred 1h at RT, filtered over a pad of Celite® and concentrated under vacuum. The crude was purified by SiO₂ column chromatography (100% EtOAc) to afford (R)-13 (40 mg, 92%) as colorless oil, as a mixture of ester/lactone 83:17. R_f = 0.32 (EtOAc). Example 4e Synthesis of (S,E)-4-hydroxy-6-((1R,2S,5R)-2-hydroxy-5-((2Z,5Z,8Z)-undeca- 2,5,8-trien-1-yl)cyclopentyl)hex-5-enoic acid (S)-IV To a solution of (S)-13 (51 mg, (1:1, v/v) was added LiOH (38 mg, 0.89 mmol, 6 eq) at RT. After 1h15 stirring, the reaction was quenched by a solution of 1M NaHSO₄ until acidic pH, extracted with EtOAc (10 mL), washed with brine, dried over MgSO4 and concentrated under vacuum. The crude product was purified by SiO2 column chromatography (100% EtOAc) to afford compound (S)-IV (38 mg, 72%) as a white powder. Rf =0.15 (100% EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 5.70 – 5.14 (m, 8H), 4.13 (d, J = 5.4 Hz, 1H), 4.01 (q, J = 5.8 Hz, 1H), 2.76 (dd, J = 5.8, 5.2 Hz, 4H), 2.56 – 2.30 (m, 3H), 2.28 – 2.13 (m, 1H), 2.14 – 1.84 (m, 7H), 1.63 – 1.45 (m, 1H), 1.43 – 1.15 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 177.97, 134.40, 132.11, 130.50, 129.06, 128.53, 128.04, 127.05, 80.66, 72.25, 54.54, 41.23, 32.75, 31.59, 30.27, 29.20, 28.12, 25.83, 25.57, 20.59, 18.09, 14.32. HRMS (ESI-) calculated for C₂₂H₃₃O₄[M-H]-361.2379, found 361.2376. [α]D²⁰(MeOH)= +22.6 (c=3.8). Example 4f Synthesis of (R,E)-4-hydroxy-6-((1R,2S,5R)-2-hydroxy-5-((2Z,5Z,8Z)-undeca- 2,5,8-trien-1-yl)cyclopentyl)hex-5-enoic acid (R)-IV To a solution of (R)-13 (50mg, 0.18mmol) in 4 mL THF/H₂O (1:1, v/v) was added LiOH (45 mg, 1.07 mmol, 6eq) at RT. After 1h15 stirring, the reaction was quenched by a solution of 1M NaHSO4 until acidic pH, extracted with EtOAc (10mL), washed with brine, dried over MgSO4 and concentrated under vacuum. The crude product was purified by SiO₂ column chromatography (100% EtOAc) to afford compound (R)-IV (27 mg, 36%) as a white powder. R_f=0.13 (100% EtOAc). ¹H NMR (300 MHz, CDCl3) δ 5.80 – 5.16 (m, 8H), 4.17 (m, 1H), 4.03 (m, Hz, 1H), 2.76 (t, J = 5.9 Hz, 4H), 2.58 – 2.33 (m, 3H), 2.20 – 1.80 (m, 8H), 1.65 – 1.15 (m, 3H), 0.94 (t, J = 7.5 Hz, 3H). HRMS (ESI-) calculated for C22H33O4[M-H]-361.2379, found 361.2376. [α]_D ²⁰(MeOH)= -4 (c=2). Example 5 – VIDD prevention studies RESULTS 4F_4t-NeuroP prevents RyR1 mediated Ca leak The term of spontaneous Ca²⁺ release events (i.e. Ca²⁺ sparks) refers to a local Ca²⁺ release events arising spontaneously in a resting muscle fiber from a cluster of RyRs also called single Ca²⁺ release unit (CRU). The measurement of Ca²⁺ sparks in a muscle fiber, provides a direct measurement in situ of the gating behavior of RyRs belonging to a single CRU. Most particularly, the frequency of Ca²⁺ sparks gives a good estimation of the open frequency of RyR1 and represents an index of RyR-mediated SR calcium leak. The inventors have previously reported a defect in RyR1 in peripheric muscle in animal model suffering from Heart failure. In a previous study, the inventors demonstrated that neuroprostanes such as 4F4t-NeuroP, lipid mediators produced by non-enzymatic free radical peroxidation of docosahexaenoic acid (DHA), were able to prevent RyR2 mediated Ca²⁺-leak in cardiomyocytes [30]. In order to test the efficiency of 4F4t-NeuroP in preventing RyR1 from a functional remodeling, the inventors tested acute application of 1µM of 4F4t-NeuroP in mouse fast twitch Extensor digitorum longus (EDL) muscle and evaluated the functional consequence on RyR1 by measuring Ca²⁺-spark frequency. The inventors thus confirmed in a mice model of heart failure obtained after permanent ligature (PMI) of the left coronary artery an impaired function of RyR1 in EDL muscle as shown by the significant increase in sparks frequency. When PMI muscle fibers were acutely incubated with 1μM 4F_4t-NeuroP, one could observe a full prevention of this RyR1- dependent leaky behavior (Figure 1). This experiment therefore confirmed the capacity of 4F4t- NeuroP to prevent RyR1 functional impairment. 4F_4t-NeuroP prevents VIDD in mice following a short MV Mice were anesthetized and mechanically ventilated for 6 hours. Mice were randomized to receive or not at the beginning of the ventilation a single IV injection of 4F4t-NeuroP at concentrations ranging from 0.01-100µM to build a dose-response curve of the force-frequency relationship in order to define the optimal concentration. In these conditions one could observe a full prevention of VIDD by 4F4t-NeuroP with a maximal effect observed for about 0.3µM (Figure 2A-B). 4F_4t-NeuroP stabilizes the complex calstabin1/RyR1 Diaphragm samples from the above experiments were frozen and solubilized to further investigate the biochemical properties of the RyR1 macromolecular complex. After 6 hours of mechanical ventilation, RyR1 immunoprecipitation revealed that VIDD was responsible for an oxidation of the channel as well as a phosphorylation on ser2844 and depletion from calstabin1. This biochemical signature of leaky RyR1 was fully prevented by 4F4t-NeuroP (Figure 2C). 4F_4t-NeuroP prevents VIDD and atrophy of diaphragmatic muscle in mice following a long MV 6 hours of MV remains a rather short time of ventilation which represents a particular interest to explore proximal pathophysiological mechanisms of VIDD. As previously reported, 6 hours of mechanical ventilation is able to induce force deficit without histological alterations. However, 12 hours of mechanical ventilation can induce muscle atrophy by a mechanism mediated by RyR1 dependent SR Ca²⁺-leak. The inventors therefore tested here the beneficial effect of 4F_4t-NeuroP after 12 hours of mechanical ventilation. The protective effect of a single injection of 4F4t-NeuroP (10µM) in these conditions was similar to that observed after 6 hours of ventilation (Figure 3A). Remarkably, after 12 hours of mechanical ventilation 10µM of 4F4t- NeuroP also prevented muscle fibers remodeling (i.e. atrophy), characteristic of VIDD. 4F_4t- NeuroP prevents the reduction of cross section area (CSA), independently of the muscle fiber phenotype (Figure 3B-C) and without changing the distribution of fiber type (slow vs fast, Figure 3D). VB558, a shorter analog of 4F4t-NeuroP prevents VIDD Due to its efficiency to stabilize RyR, the 4F_4t-NeuroP (WO2015197562) was a very interesting biomolecule. However, its synthesis is rather long and costly and thus limits its use for therapeutic purposes. The inventors thus screened several analogs of 4F4t-NeuroP to identify compounds which could present at least the same efficiency than 4F4t-NeuroP but for which the synthesis could be more practicable. The screening was performed in an in vitro model of arrythmias which is characterized by a RyR dysfunction (as described in WO2014086819). VB558 was selected as the most promising candidate since its synthesis only involves 17 steps contrary to 24 steps for the 4F_4t-NeuroP (Figure 4A). As for 4F4t-NeuroP, VB558 was injected intravenously into the mouse at a concentration of 1 and 10µM before ventilating the mice for 6 hours. Both concentrations demonstrate significant protection against mechanical ventilation in a range similar to that was obtained with 4F4t-NeuroP (Figure 4B). VB558 prevents VIDD in piglets after 72 hours of ventilation To validate the potential clinical usefulness of neuroprostanes in the prevention of VIDD, the inventors decided to test the efficacy of VB558 in a piglet model of VIDD as previously published^17,18. In a first set of experiment, a pharmacokinetic study was performed on 3 control pig injected with a single bolus of VB558 (0.250 mg.kg^-1). Blood samples were collected every regularly during 12 hours to evaluate the plasmatic concentration of VB558. This demonstrated a rapid plasmatic peak between the first 5-10 minutes which dissipated rapidly within an hour suggesting a fast biodistribution of the compound (Figure 5A). In order to test the preventing effect of VB558 in the piglet model, the protocol of IV injection was slightly adapted to the duration of the mechanical ventilation (i.e 72 hours). The inventors injected a bolus of 0.250mg.kg^-1 then a maintenance dose of 0.025mg.kg^-1 every 12 hours (figure 5B). The VB558 group was compared to a group of piglets (placebo) receiving the same amount of solvent (methanol) (Figure 5B). By measuring the trans-diaphragmatic pressure at different stimulation frequencies of the phrenic nerve, the inventors were able to build the equivalent of an in vivo force-frequency relationship that is a Pdi-frequency relationship at the beginning of the anesthesia (D0). It appears clearly that in control piglets, 72 hours of mechanical ventilation induced a large and significant reduction of the Pdi that is fully prevented by VB558. VB558 interaction with Prostaglandin receptors Prostaglandin (or prostanoid) receptors represent a family of cell surface membrane receptors known to bind and respond principally to metabolites of the polyunsaturated fatty acid (PUFA), arachidonic acid. As some of them are known to modulate cAMP production or intracellular calcium concentration, and based on the chemical structure of neuroprostanes (i.e DHA derivatives), the inventors performed an in vitro binding assay to specifically evaluate the potential agonist or antagonist effect of VB558 on established prostanoid receptors. Results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% are considered to represent significant effects of the test compounds. Such effects were not observed at any of the receptors studied here suggesting that the effect of VB558 detailed above are independent of prostanoid receptors. DISCUSSION: While the vast majority of patients in intensive care patients are easily weaned from mechanical ventilation (MV), about 25% of patients experience a difficult weaning which requires an extension of this mechanical ventilation. However, the use of MV leads to significant damage to the respiratory muscles which is characterized by progressive muscle weakness and histological remodeling of the respiratory muscles which further reduce the chances of weaning. This is even more true in patients with aggravating factors such as malnutrition, chronic electrolyte abnormalities, hyperglycemia, excessive resistive and elastic loads, corticosteroids, exposure to muscle relaxants, sepsis and impaired heart function²⁸. To date, no therapeutic strategy has proven its effectiveness in intensive care patients to prevent VIDD. Our team has demonstrated in mouse, piglet models of VIDD and also in patients, that a remodelling of RyR1 appears as a proximal pathophysiological mechanism^15,19. More precisely all model of VIDD exhibit the biochemical signature of leaky RyR1 channels (i.e. Phosphorylation, oxidation and dissociation of calcstabin1) and evidence of intracellular Ca²⁺ leak. Thus, RyR1 dysfunction is driven by β-adrenergic signaling pathway in synergy with MV- induced oxidative stress, which has been extensively studied in VIDD⁴. Indeed, RyRs are highly sensitive to oxidative/nitrosative stress in skeletal muscle and in other tissues. Therefore, This RyR remodeling occurs in other chronic or inherited disease including heart failure, diabetes, Duchenne muscular dystrophy^23-27. Postranslational modification of RyR1 also progresses with aging and partially accounts for age-dependent muscle weakness²⁴. The inventors demonstrate in this work, that oxidized derivative of DHA including 4F_4t- NeuroP and its shorter derivative VB558 prevent with a high efficiency VIDD both in a murin and porcin model of VIDD. This effect is associated with a normalization of RyR function. Although the inventors cannot exclude a direct effect of 4F_4t-NeuroP and VB558 on RyR, in contrast to Rycal effects²⁸, the inventors also observed that both compounds prevent RyR oxidation, and phosphorylation, suggesting an upstream mechanism rather than a direct effect on RyR as the inventors previously reported^21,29. To date, only spontaneous ventilatory cycles and perhaps phrenic nerve stimulation appear to diminish the severity of VIDD in humans but several pathways are currently being examined using animal models to identify a pharmacological option. The inventors provide here the proof of concept that VB558 may be an efficient molecule to prevent VIDD in patient. The need for such therapy is all the more urgent in the current context of the COVID- 19 pandemic where the number of patients in intensive care has exploded during peaks of contamination. Finally, such pharmacological strategy could be of interest in all pathological situations as described above where RyR function is altered (i.e., cardiac diseases, muscle myopathies, sarcopenia, cachexia, diabetes, neurodegenerative disorders). Example 6: DMD Studies The inventors then tested the impact of VB558 on the diastolic level of Calcium in ventricular cardiomyocytes derived from Duchenne muscular dystrophy (DMD). The results are shown in Figure 6. These data demonstrate that RyR2 dysfunction in DMD may be prevented by VB558 supporting its therapeutic interest in this pathology (Figure 6A-B). Example 7: Study of calcium transients and cell contraction Compounds 20,21,22-trinor-4(RS)-4-F4t-NeuroP (compound of Formula III, VB574) and monohydroxylated derivative of 4-F_4t-NeuroP (Compound IV) were evaluated for their anti- arrhythmic properties. Calcium transients and cell contraction was measured by the photometric system ionOptix®. a) General principle of the measurements The photometric system IonOptix® can provide real-time, simultaneous acquisition of fluorescence photometry with sarcomere length measurements. For the study of isolated myocytes, the system includes a pacemaker that offers full control of the stimulation pulse duration, the frequency and the voltage. Thus, the photometric system IonOptix® puts in correlation the calcium transients and the shortening of the electrically stimulated myocytes (1 Hz, 20 V, Figure 7). Calcium was studied by the use of a ratiometric fluorescent calcium probe (indo-1-AM, excitation wavelength 360 ± 10 nm, emission wavelength at 405 ± 10 nm and 485 ± 10 nm). b) Protocol To measure the intracellular calcium, the first step was to bring ventricular myocytes load into contact with an amount of indo-1-AM. To make it liposoluble, indo-1 was esterified on its carboxylic functions to give indo-1-AM. Once present in the cell, esterases allow the release of Indo-1 carboxylic functions enabling it to bind to the intracellular calcium. The incorporation time was predetermined to 30 minutes. This time was chosen following experiments using different times of incubation and 30 minutes was the time giving a good ratio/noise ratio and no obvious perturbation of cellular calcium homeostasis. The incubation time of the probe is critical because too low load generates a weak signal while excessive exposure will excessively increase the buffering capacity of the cytoplasm for calcium. Once loaded and the cells arranged on the measuring system by means of a tank containing Tyrode salt solution (450μL), the probe was excited by a xenon lamp at a wavelength of 360nm. Through an optical wavelength filter, the apparatus collects the fluorescence emitted from the Indo-1 at two different wavelengths: 405 ± 10 nm and 485 ± 10nm. The first wavelength represents the fluorescence of the probe bound to calcium and the second wavelength represents the fluorescence of the free probe. The ratio of these two wavelengths reflects the concentration of intracellular calcium. It is thus possible to observe calcium transients in ventricular myocytes systole but also to observe the diastolic calcium when the stimulation is stopped. To measure the contraction, striation of cardiac cells due to the presence of sarcomeres was used. This striation can be scanned and acquired by a computer. The recorded signal is similar to a sine function. This function was then treated mathematically by a Fourier transformation, which allows obtaining the period of the sinusoidal or sarcomere length. The experimental protocol further addresses the changes in intracellular calcium transients and the changes in peaks of cell contraction by analysing sarcomere shortening, during 30 seconds of electrical stimulation at 1 Hz, followed by 30 seconds interspersed pause (Figure 7). With this protocol, the goal is to identify arrhythmic events, i.e irregularities in the rate of contractions then to study the effects of 4-(RS)-4-F4T-neuroprostane derivatives on these events. To reproduce the sympathetic tone that characterizes the murine model, the cells are subjected to 10 nM isoproterenol. This molecule in stimulating β-adrenergic system, will then lead to an increase in the amplitude of contractions but also will promote the development of ExtraSystole Ventricular contraction (ESV) as shown in Figure 7. These ESV are consecutive to abnormal functioning of type 2 ryanodine receptor (RyR). Thus, to evaluate the potential RyR stabilizing effect of the 4-F4T-neuroprostane derivatives (compounds III and IV), the compounds were applied, and the percentage of arrhythmic cells was measured. It has been found that compound III (Figure 8) and compound IV (Figure 9) show anti- arrhythmic properties indicative of an interaction with the RyR. REFERENCES: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure. 1. Kushnir A, Marks AR. Ryanodine receptor patents. Recent Pat Biotechnol. 2012 Dec;6(3):157-66. 2. Powers SK, Kavazis AN, Levine S. Prolonged mechanical ventilation alters diaphragmatic structure and function. Crit Care Med. 2009 Oct;37(10 Suppl):S347-53. 3. Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, Zhu J, Sachdeva R, Sonnad S, Kaiser LR, Rubinstein NA, Powers SK, Shrager JB. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008 Mar 27;358(13):1327-35. 4. Jaber S, Jung B, Matecki S, Petrof BJ. Clinical review: ventilator-induced diaphragmatic dysfunction--human studies confirm animal model findings! Crit Care. 2011 Mar 11;15(2):206. 5. Vassilakopoulos T, Petrof BJ. Ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med. 2004 Feb 1;169(3):336-41. 6. Tobin MJ, Laghi F, Jubran A. Narrative review: ventilator-induced respiratory muscle weakness. Ann Intern Med. 2010;153(4):240-245. doi:10.7326/0003-4819-153-4- 201008170-00006 7. Esteban A, Ferguson ND, Meade MO, Frutos-Vivar F, Apezteguia C, Brochard L, Raymondos K, Nin N, Hurtado J, Tomicic V, González M, Elizalde J, Nightingale P, Abroug F, Pelosi P, Arabi Y, Moreno R, Jibaja M, D'Empaire G, Sandi F, Matamis D, Montañez AM, Anzueto A; VENTILA Group. Evolution of mechanical ventilation in response to clinical research. Am J Respir Crit Care Med. 2008 Jan 15;177(2):170-7. 8. Shanely RA, Zergeroglu MA, Lennon SL, Sugiura T, Yimlamai T, Enns D, Belcastro A, Powers SK. Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative injury and increased proteolytic activity. Am J Respir Crit Care Med. 2002 Nov 15;166(10):1369-74. 9. Falk DJ, Kavazis AN, Whidden MA, et al. Mechanical ventilation-induced oxidative stress in the diaphragm: role of heme oxygenase-1. Chest. 2011;139(4):816-824. doi:10.1378/chest.09-2787. 10. Zergeroglu MA, McKenzie MJ, Shanely RA, Van Gammeren D, DeRuisseau KC, Powers SK. Mechanical ventilation-induced oxidative stress in the diaphragm. J Appl Physiol (1985). 2003 Sep;95(3):1116-24. 11. Betters JL, Criswell DS, Shanely RA, Van Gammeren D, Falk D, Deruisseau KC, Deering M, Yimlamai T, Powers SK. Trolox attenuates mechanical ventilation-induced diaphragmatic dysfunction and proteolysis. Am J Respir Crit Care Med. 2004 Dec 1;170(11):1179-84. 12. Picard M, Jung B, Liang F, Azuelos I, Hussain S, Goldberg P, Godin R, Danialou G, Chaturvedi R, Rygiel K, Matecki S, Jaber S, Des Rosiers C, Karpati G, Ferri L, Burelle Y, Turnbull DM, Taivassalo T, Petrof BJ. Mitochondrial dysfunction and lipid accumulation in the human diaphragm during mechanical ventilation. Am J Respir Crit Care Med. 2012 Dec 1;186(11):1140-9. 13. Kavazis AN, Talbert EE, Smuder AJ, Hudson MB, Nelson WB, Powers SK. Mechanical ventilation induces diaphragmatic mitochondrial dysfunction and increased oxidant production. Free Radic Biol Med. 2009 Mar 15;46(6):842-50. 14. Mrozek S, Jung B, Petrof BJ, Pauly M, Roberge S, Lacampagne A, Cassan C, Thireau J, Molinari N, Futier E, Scheuermann V, Constantin JM, Matecki S, Jaber S. Rapid onset of specific diaphragm weakness in a healthy murine model of ventilator-induced diaphragmatic dysfunction. Anesthesiology. 2012 Sep;117(3):560-7. 15. Matecki S, Dridi H, Jung B, Saint N, Reiken SR, Scheuermann V, Mrozek S, Santulli G, Umanskaya A, Petrof BJ, Jaber S, Marks AR, Lacampagne A. Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation. Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):9069-74. 16. Maes K, Testelmans D, Powers S, Decramer M, Gayan-Ramirez G. Leupeptin inhibits ventilator-induced diaphragm dysfunction in rats. Am J Respir Crit Care Med.2007 Jun 1;175(11):1134-8. 17. McClung JM, Van Gammeren D, Whidden MA, et al. Apocynin attenuates diaphragm oxidative stress and protease activation during prolonged mechanical ventilation. Crit Care Med. 2009;37(4):1373-1379. 18. Jung B, Constantin JM, Rossel N, Le Goff C, Sebbane M, Coisel Y, Chanques G, Futier E, Hugon G, Capdevila X, Petrof B, Matecki S, Jaber S. Adaptive support ventilation prevents ventilator-induced diaphragmatic dysfunction in piglet: an in vivo and in vitro study. Anesthesiology. 2010 Jun;112(6):1435-43. 19. Matecki S, Jung B, Saint N, Scheuermann V, Jaber S, Lacampagne A. Respiratory muscle contractile inactivity induced by mechanical ventilation in piglets leads to leaky ryanodine receptors and diaphragm weakness. J Muscle Res Cell Motil. 2017 Feb;38(1):17-24. 20. Dridi H, Yehya M, Barsotti R, Reiken S, Angebault C, Jung B, Jaber S, Marks AR, Lacampagne A, Matecki S. Mitochondrial oxidative stress induces leaky ryanodine receptor during mechanical ventilation. Free Radic Biol Med. 2020 Jan;146:383-391. 21. Roy J, Oger C, Thireau J, Roussel J, Mercier-Touzet O, Faure D, Pinot E, Farah C, Taber DF, Cristol JP, Lee JC, Lacampagne A, Galano JM, Durand T, Le Guennec JY. Nonenzymatic lipid mediators, neuroprostanes, exert the antiarrhythmic properties of docosahexaenoic acid. Free Radic Biol Med. 2015 Sep;86:269-78. 22. Oger C, Bultel-Poncé V, Guy A, Balas L, Rossi JC, Durand T, Galano JM. The handy use of Brown's P2-Ni catalyst for a skipped diyne deuteration: application to the synthesis of a [D4]-labeled F4t-neuroprostane. Chemistry. 2010 Dec 17;16(47):13976- 80. 23. Bellinger AM, Reiken S, Carlson C, Mongillo M, Liu X, Rothman L, Matecki S, Lacampagne A, Marks AR. Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med. 2009 Mar;15(3):325-30. 24. Andersson DC, Betzenhauser MJ, Reiken S, Meli AC, Umanskaya A, Xie W, Shiomi T, Zalk R, Lacampagne A, Marks AR. Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metab. 2011 Aug 3;14(2):196-207. 25. Donoso P, Sanchez G, Bull R, Hidalgo C. Modulation of cardiac ryanodine receptor activity by ROS and RNS. Front Biosci (Landmark Ed). 2011 Jan 1;16:553-67. 26. Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D'Ascia SL, Cannone M, Marziliano N, Trimarco B, Guise TA, Lacampagne A, Marks AR. Calcium release channel RyR2 regulates insulin release and glucose homeostasis. J Clin Invest. 2015 May;125(5):1968-78. 27. Lacampagne A, Liu X, Reiken S, Bussiere R, Meli AC, Lauritzen I, Teich AF, Zalk R, Saint N, Arancio O, Bauer C, Duprat F, Briggs CA, Chakroborty S, Stutzmann GE, Shelanski ML, Checler F, Chami M, Marks AR. Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer's disease-like pathologies and cognitive deficits. Acta Neuropathol. 2017 Nov;134(5):749-767. 28. Bellinger AM, Reiken S, Dura M, Murphy PW, Deng SX, Landry DW, Nieman D, Lehnart SE, Samaru M, LaCampagne A, Marks AR. Remodeling of ryanodine receptor complex causes "leaky" channels: a molecular mechanism for decreased exercise capacity. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2198-202. 29. Fauconnier J, Meli AC, Thireau J, Roberge S, Shan J, Sassi Y, Reiken SR, Rauzier JM, Marchand A, Chauvier D, Cassan C, Crozier C, Bideaux P, Lompré AM, Jacotot E, Marks AR, Lacampagne A. Ryanodine receptor leak mediated by caspase-8 activation leads to left ventricular injury after myocardial ischemia-reperfusion. Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13258-63.

Claims

CLAIMS: 1. A method of treating a disease associated with a RyR dysfunction in a subject in need thereof comprising administering the subject with a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof: R1 represents H or OH, R₂ represents a linear C₁-C₁₀ alkyl group, or a C₂-C₁₀ alkenyl group, with the provisio that when R2 represents , R1 represents H. 2. The method of claim 1, wherein the compound of Formula I is such that R₂ is a group chosen from a group of Formulae a, b and c: .

3. The method according to claim 1 or 2, wherein the compound of Formula I is chosen from:

, said compound of Formula I having a structure of Formula II, Formula III, Formula IV, Formula S-IV or Formula R-IV.

4. The method of anyone of claims 1 to 3, wherein the disease associated with a RyR dysfunction is ventilator-induced diaphragmatic dysfunction.

5. The method of claim 4, wherein the subject needs artificial respiratory support because he suffers from respiratory failure and/or heart failure which, can be aggravated by sepsis, metabolic disorder, neuromuscular diseases, or surgery along with post-surgical recovery.

6. The method of claim 4, wherein the subject suffers from a disease for which the worsening of the symptoms has led the subject to need mechanical ventilation, in particular wherein the disease is selected from the group consisting of Chronic Obstructive Pulmonary Disease (COPD), pneumonia, sepsis, Acute Respiratory Distress Syndrome (ARDS), Severe Acute Respiratory Syndrome (SARS) and cystic fibrosis (CF).

7. The method of claim 6, wherein the Severe Acute Respiratory Syndrome is COVID-19.

8. The method of claim 4, wherein the subject suffers from a trauma.

9. The method of any one of claim 4 to 8, wherein the ventilator-induced diaphragmatic dysfunction results from prolonged controlled mechanical ventilation (MV) greater than 12 hours, in particular wherein the compound of Formula I is administered before MV, immediately after MV initiation, during MV, and/or immediately after MV.

10. The method anyone of claims 1 to 3, wherein the disease is selected from the group consisting of cardiac disorders and diseases, muscle fatigue, musculoskeletal disorders and diseases, Central Nervous System (CNS) disorders and diseases, cognitive dysfunction, bone disorders and diseases, malignant hyperthermia, diabetes, sudden cardiac death, and sudden infant death syndrome, in particular wherein the cardiac disorders is selected from the group consisting of exercise-induced irregular heartbeat disorders and diseases, heart failure, congestive heart failure, chronic heart failure, acute heart failure, systolic heart failure, diastolic heart failure, acute decompensated heart failure, cardiac ischemia/reperfusion (I/R) injury (including I/R injury following coronary angioplasty or following thrombolysis during myocardial infarction (MI)), chronic obstructive pulmonary disease, high blood pressure, and irregular heartbeat disorders and diseases such as atrial and ventricular arrhythmia, atrial and ventricular fibrillation, atrial and ventricular tachyarrhythmia, atrial and ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-induced variants thereof, in particular wherein the musculoskeletal disorders and diseases is selected from the group consisting of skeletal muscle fatigue, central core diseases, exercise-induced skeletal muscle fatigue, bladder disorders, incontinence, age- associated muscle fatigue, sarcopenia, congenital myopathies, cancer cachexia, myopathy with cores and rods, mitochondrial myopathies [e.g., Kearns-Sayre syndrome, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) syndrome, and MERRF (myoclonus epilepsy with ragged-red fibers) syndrome], endocrine myopathies, muscular glycogen storage diseases [e.g., Pompe's disease, Andersen's disease, and Cori's diseases], myoglobinurias [e.g., McArdle's disease, Tarui disease, and DiMauro disease], dermatomyositis, myositis ossificans, familial periodic paralysis, polymyositis, inclusion body myositis, neuromyotonia, stiff-man syndrome, malignant hyperthermia, common muscle cramps, tetany, myasthenia gravis, and muscular dystrophy, in particular, wherein the muscular dystrophy is selected from the group consisting of Duchenne Muscular Dystrophy (DMD), Becker's Muscular Dystrophy (BMD), Limb Girdle Muscular Dystrophy (LGMD), Congenital Muscular Dystrophy (CMD), distal muscular dystrophy, facioscapulohumeral dystrophy, myotonic muscular dystrophy, Emery-Dreifuss muscular dystrophy, and oculopharyngeal muscular dystrophy, or wherein the cognitive disorders is selected from the group consisting of Alzheimer's Disease (AD), memory loss, age-dependent memory loss, post-traumatic stress disorder (PTSD), a neuropathy, seizures, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), Parkinson's Disease (PD), schizophrenia, bipolar disorder; and major depression.

11. A compound of Formula IA or a pharmaceutically acceptable salt thereof: R1 represents H or OH, R2 represents a linear C1-C10 alkyl group, a C2-C7 alkenyl group comprising 1 double bond, or a C2-C10 alkenyl group comprising 2 double bonds, with the provisio that when R₂ represents , R₁ represents H, in particular wherein R2 represents a group chosen from a group of Formulae a, b and c: .

12. The compound according to claim 11, wherein the compound of Formula IA is chosen from: , said compound of Formula IA having a structure of Formula IIA, Formula IIIA, Formula IVA, Formula S-IVA or Formula R-IVA.

13. A compound of Formula IA according to claims 11 or 12, or a compound of Formula I as defined in any of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in a method for treatment of the human or animal body.

14. A pharmaceutical composition comprising a compound of Formula I, or a compound of Formula IA, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, said compound of Formula I being as defined in anyone of claims 1 to 3, said compound of Formula IA being as defined in anyone of claims 11 or 12.

15. A process for preparing the compound of Formula I, said compound of Formula I being as defined in anyone of claims 1 to 3, wherein the process comprises: a step A of oxidation of an alcohol of Formula V to give an aldehyde of Formula VI, an group, a protecting group, more in particular a t-butyldimethylsilyl protecting group, R₄ being methyl or ethyl, R₅ being H or OR₃, wherein R₃ is as defined above. a step B of olefination of the aldehyde of Formula VI to give an olefin of Formula VII, as R₂ being as defined for in claims 1 to 3 for Formula I, a step C of deprotection of the hydroxyl groups in Formula VII to give an ester of Formula VIII as step R₁ and R₂ being defined in claims 1 to 3 for Formula I. A step D of hydrolysis of the ester of Formula VIII to give a compound of Formula I, R4 being as defined in step A, R₁ and R₂ being as defined in claims 1 to 3 for Formula I.