Methods and compositions for treating pulmonary inflammatory injury

Abstract

Disclosed are compositions and methods related to the treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), including viral pneumonia (such as COVID-19 pneumonia), in which the subject has a PaO2 / FiO2 (P / F) ratio of less than 200 and comprises an intracellular calcium signaling inhibitor (such as Auxora), alone or in combination with a corticosteroid and / or an immunosuppressant. Such compositions and methods may be used to reduce the release of pro-inflammatory cytokines that may lead to ALI and / or ARDS.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 301,276, filed January 20, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent severe syndromes of acute respiratory failure with considerable morbidity and mortality. In the current COVID-19 pandemic, in patients infected with SARS-CoV-2, their immune response can lead to a “cytokine storm” that can later result in ALI, ARDS, death, or permanent impairment of lung function in survivors. Summary of the Invention

[0003] In one aspect, the disclosure provides a method for treating acute lung injury (ALI), acute respiratory distress syndrome (ARDS), COVID-19 pneumonia, bacterial pneumonia, viral pneumonia, acute pancreatitis, or a combination thereof in a subject, comprising administering a therapeutically effective amount of an intracellular calcium signaling inhibitor to the subject, wherein the subject has a PaO2 / FiO2 (P / F) ratio of about 150 or less, and the subject has been administered at least two doses of the intracellular calcium signaling inhibitor.

[0004] In another aspect, the disclosure provides a method for treating acute lung injury (ALI), acute respiratory distress syndrome (ARDS), COVID-19 pneumonia, bacterial pneumonia, viral pneumonia, acute pancreatitis, or a combination thereof in a subject, comprising administering to the subject a therapeutically effective amount of a corticosteroid and / or an immunosuppressant and an intracellular calcium signaling inhibitor, wherein the subject has a PaO2 / FiO2 (P / F) ratio of about 150 or less.

[0005] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0006] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings.

[0007] [Figure 1] FIG. 1 shows an example of a clinical trial design evaluating CRAC inhibitors in patients with severe COVID-19 pneumonia. [Diagram 2] Graph showing patient mortality at days 30 and 60 in patients treated with placebo or Auxora. [Diagram 3] 1 is a plot showing mortality through day 60 in patients treated with placebo or Auxora using the KM efficacy analysis set. [Figure 4] FIG. 1 shows an example of a clinical trial design evaluating CRAC inhibitors in mechanically ventilated patients. [Diagram 5] FIG. 1 shows a clinical trial of patients receiving Auxora with different PaO2 / FiO2 ranges. [Figure 6] FIG. 1 shows an example of a clinical trial design to evaluate combination therapy with CRAC inhibitors and tocilizumab in patients with severe COVID-19 pneumonia. [Figure 7] FIG. 1 shows imputed PaO2 / FiO2 data. [Figure 8] FIG. 1 shows the timeline of the clinical trial. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The methods and compositions disclosed herein are used to regulate intracellular calcium to treat or prevent acute lung injury (ALI) and / or acute respiratory distress syndrome (ARDS). In some embodiments, the methods and compounds provided herein regulate CRAC channel activity. In another embodiment, the methods and compounds provided herein reduce the number of functional CRAC channels. In some embodiments, the methods and compounds described herein are CRAC channel blockers or CRAC channel modulators. In some embodiments, the methods and compounds described herein regulate the PaO2 / FiO2 (P / F) ratio of a subject. In some embodiments, the methods and compounds described herein may further include one or more additional therapeutic agents, such as corticosteroids and / or immunosuppressants.

[0009] Calcium plays a critical role in cell function and survival. Specifically, calcium is a key element in the transduction of signals into and within cells. Cellular responses to growth factors, neurotransmitters, hormones, and a variety of other signaling molecules are initiated through calcium-dependent processes.

[0010] Nearly all cell types express, in some way, cytoplasmic Ca that controls cellular function or triggers specific responses. 2+ It relies on the generation of a signal, cytoplasmic Ca 2+ Signals control a wide range of cellular functions, ranging from short-term responses such as contraction and secretion to long-term regulation of cell growth and proliferation. Typically, these signals involve the release of Ca from intracellular stores such as the endoplasmic reticulum (ER). 2+ Release of Ca across the plasma membrane 2+ In one example, cell activation begins with agonist binding to a surface membrane receptor, coupled to phospholipase C (PLC) by a G protein mechanism. PLC activation leads to the production of inositol 1,4,5-triphosphate (IP3), which promotes Ca influx from the ER. 2+ It activates IP3 receptors, which causes the release of ER Ca 2+A decrease in β-lactamase signaling activates plasma membrane store-operated calcium (SOC) channels.

[0011] Store-operated calcium (SOC) entry is a process that, although not limited to, increases intracellular Ca 2+ It is the cellular physiological processes that control such diverse functions as store refilling (Putney et al., Cell 75, 199-201, 1993), activation of enzyme activity (Fagan et al., J. Biol. Chem. 275:26530-26537, 2000), gene transcription (Lewis, Annu. Rev. Immunol. 19:497-521, 2001), cell proliferation (Nunez et al., J. Physiol. 571.1, 57-73, 2006), and cytokine release (Winslow et al., Curr. Opin. Immunol. 15:299-307, 2003). In some non-excitable cells, such as blood cells, immune cells, hematopoietic cells, T lymphocytes, and mast cells, pancreatic acinar cells (PAC), epithelial and ductal cells of other glands (e.g., salivary glands), endothelial and endothelial progenitor cells (e.g., pulmonary endothelial cells), SOC influx occurs through a type of SOC channel, the calcium release-activated calcium (CRAC) channel.

[0012] The calcium entry mechanism is termed store-operated calcium entry (SOCE). Stromal interaction molecule (STIM) proteins are essential components of SOC channel function and serve as sensors to detect calcium depletion from intracellular stores and activate SOC channels.

[0013] Preclinical and animal studies provided herein have shown that CRAC inhibitors such as N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide (Compound 1) can treat COVID-19 pneumonia, other viral pneumonia, and ALI or ARDS. Compound 1 has been tested in acutely ill acute pancreatitis (AP) patients (as well as severe and / or critical COVID-19 pneumonia patients) with systemic inflammatory response syndrome (SIRS) and hypoxemia. Treatment of a subject with a CRAC inhibitor can result in a rapid reduction of IL-6, IL-2, IL-17, TNFα, and / or other inflammatory cytokines in the subject. Treatment of a subject with a CRAC inhibitor such as Compound 1 can also result in the preservation of lung function and protection from injury.

[0014] Calcium homeostasis Cellular calcium homeostasis is the result of the sum of regulatory systems involved in controlling calcium levels and movement within the cell, which is achieved, at least in part, by calcium binding and intracellular calcium movement in and out of the cell across the plasma membrane, as well as across membranes of intracellular organelles, including, for example, the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria, and endocytic organelles, including endosomes and lysosomes.

[0015] Movement of calcium across cell membranes is carried out by specialized proteins. For example, calcium from the extracellular space can enter cells through various calcium channels and sodium / calcium exchangers, and is actively pumped out of cells by calcium pumps and sodium / calcium exchangers. Calcium can also be released from internal stores via inositol trisphosphate or ryanodine receptors and can be taken up by these organelles by calcium pumps.

[0016] Calcium can enter cells by any of several general classes of channels, including, but not limited to, voltage-operated calcium (VOC) channels, ligand-gated calcium channels, store-operated calcium (SOC) channels, and inversely operating sodium / calcium exchangers. VOC channels are activated by membrane depolarization and are found in excitable cells such as nerves and muscles, but are largely absent from non-excitable cells. Under some circumstances, Ca 2+ The Na+-Ca function works in reverse. 2+ It can enter cells via the exchanger.

[0017] Endocytosis provides another process by which cells can take up calcium from the extracellular medium to endosomes. Additionally, some cells, such as exocrine gland cells, can release calcium by exocytosis.

[0018] Cytoplasmic calcium concentration is tightly controlled, usually with a resting level estimated to be about 0.1 μM in mammalian cells, while extracellular calcium concentration is typically about 2 mM. This tight control facilitates the transduction of signals into and within cells by transient calcium influx across the plasma membrane and membranes of intracellular organelles. Cells have a variety of intracellular calcium transport and buffering systems responsible for shaping intracellular calcium signals and maintaining low resting cytoplasmic calcium concentrations. In resting cells, the main components involved in maintaining basal calcium levels are calcium pumps, which leaky pathways in both the endoplasmic reticulum and the plasma membrane. Disturbances in resting cytosolic calcium levels can affect the transmission of calcium-dependent signals and cause defects in many cells. For example, cell proliferation involves a prolonged calcium signaling sequence. Other cellular processes involving calcium signaling include, but are not limited to, secretion, transcription factor signaling, and fertilization.

[0019] Cell surface receptors that activate phospholipase C (PLC) accept cytosolic Ca from intracellular and extracellular sources. 2+ The first [Ca 2+ A transient increase in intracellular calcium concentration (Ca) is caused by the release of Ca from the endoplasmic reticulum (ER). 2+ This is due to the release of Ca, which is triggered by the opening of IP3 receptors in the ER by the PLC product inositol-1,4,5-trisphosphate (IP3) (Streb et al., Nature, 306, 67-69, 1983). This is followed by a sustained release of Ca across the plasma membrane in a subsequent step. 2+ Influx occurs through specialized store-operated calcium (SOC) channels in the plasma membrane (in non-excitable cells such as immune PAC cells, the SOC channels are calcium release-activated calcium (CRAC) channels). Store-operated Ca 2+ Inflow (SOCE) is Ca 2+ The emptying of the store itself leads to the Ca 2+ SOCE is a process that activates Ca channels to help replenish stores (Putney, Cell Calcium, 7, 1-12, 1986; Parekh et al., Physiol. Rev. 757-810, 2005). 2+ It not only provides a constant supply of Ca but also, by itself, controls essential functions such as gene expression, cellular metabolism, and exocytosis. 2+ A signal can be generated (Parekh and Putney, Physiol. Rev. 85, 757-810 (2005)).

[0020] In lymphocytes and mast cells, activation of antigen or Fc receptors, respectively, releases Ca from intracellular stores. 2+ Ca release via CRAC channels in the plasma membrane 2+ Some immune cells, including monocytes / macrophages, neutrophils, and dendritic cells, require Ca influx from intracellular stores. 2+ release of Ca via CRAC channels in the plasma membrane 2+Influx can occur without Fc receptor activation. 2+ Elevated levels of NFAT activate calcineurin, a phosphatase that regulates the transcription factor NFAT. In resting cells, NFAT is phosphorylated and present in the cytoplasm, but upon dephosphorylation by calcineurin, NFAT translocates to the nucleus and activates various gene programs depending on the stimulating conditions and cell type. In response to infection and during transplant rejection, NFAT partners with the transcription factor AP-1 (Fos-Jun) in the nucleus of "effector" T cells, thereby transactivating cytokine genes, genes that control T cell proliferation, and other genes that orchestrate active immune responses (Rao et al., Annu Rev Immunol., 1997;15:707-47). In contrast, in T cells that recognize self-antigens, NFAT is activated in the absence of AP-1, activating a transcriptional program known as "anergy," which suppresses the autoimmune response (Macian et al., Transcriptional mechanisms underlying lymphocyte tolerance. Cell. 2002 Jun 14;109(6):719-31). In a subclass of T cells known as regulatory T cells, which suppress autoimmunity mediated by autoreactive effector T cells, NFAT partners with the transcription factor FOXP3 to activate genes responsible for suppressor function (Wu et al. Cell, 2006 Jul 28;126(2):375-87; Rudensky AY, Gavin M, Zheng Y. Cell. 2006 Jul 28;126(2):253-256).

[0021] The endoplasmic reticulum (ER) carries out various processes. The ER transports Ca 2+ Sink and agonist-sensitive Ca 2+ In the latter case, it acts both as a Ca store and a lumen in which protein folding / processing occurs. 2+Dependent chaperone proteins ensure that newly synthesized proteins are correctly folded and directed to their appropriate destination. The ER is also involved in vesicle trafficking, release of stress signals, control of cholesterol metabolism, and apoptosis. Many of these processes are mediated by luminal Ca 2+ and protein misfolding, and the ER stress response and apoptosis all require prolonged Ca 2+ The process requires a finite amount of Ca. 2+ ER Ca 2+ The Ca content during stimulation 2+ However, to maintain the functional integrity of the ER, it is clear that the Ca concentration must decrease after Ca release. 2+ It is essential that the content is not too low, or at least maintained at a low level. 2+ Replenishment of the ER with ER Ca is a central process for all eukaryotic cells. 2+ The decrease in Ca content is due to store-operated Ca in the plasma membrane. 2+ To activate the channel, this Ca 2+ The main function of the influx pathway is to transport ER Ca, which is required for proper protein synthesis and folding. 2+ However, store-operated Ca 2+ The channel has another important role.

[0022] Our understanding of store-operated calcium entry relies on the process of emptying stores to release Ca 2+ Release activated Ca 2+ The Ca current in mast cells is called ICRAC 2+ This was brought about by electrophysiological studies that established that ICRAC is a voltage-free, inwardly rectifying, Ca 2+ It is remarkably selective for Ca2+, which is found in several cell types, mainly of hematopoietic origin. ICRAC is not the only store-operated current, and it is now clear that store-operated influx is a Ca2+ current with different properties in different cell types. 2+It is clear that ICRAC encompasses a family of store-operated Ca permeability channels. 2+ This current remains a popular model for testing store-operated influx.

[0023] Store-operated calcium channels are ER Ca 2+ Store-operated Ca2+ can be activated by any procedure that empties the stores. It does not seem to matter how the stores are emptied; the net effect is to activate store-operated Ca2+. 2+ Physiologically, store emptying is the activation of influx of IP3 or other Ca 2+ Increased levels of the release signal and subsequent Ca release from stores 2+ However, there are several other ways to empty the stores. These methods include: 1) Elevation of cytosolic IP3 (after receptor stimulation or by dialysing the cytosol with IP3 itself or related analogs such as the non-metabolizable analog Ins(2,4,5)P3), 2) Ca to permeabilize the ER membrane 2+ application of ionophores (e.g., ionomycin); 3) Ca leaking from the store 2+ High concentrations of Ca prevent store replenishment by chelating Ca 2+ dialysis of the cytoplasm with a chelating agent (e.g., EGTA or BAPTA); 4) Sarcoplasmin / endoplasmic reticulum Ca2+ receptor antagonists such as thapsigargin, cyclopiazonic acid, and di-tert-butylhydroquinone 2+ - Exposure to ATPase (SERCA) inhibitors, 5) sensitizing IP3 receptors to resting levels of InsP3 with drugs such as thimerosal; and 6) Membrane-permeable metal Ca such as N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) 2+ The chelating agent is loaded directly into the store. By mass action, TPEN depletes total store Ca such that a store depletion-dependent signal is generated.2+ without changing the free intraluminal Ca 2+ Decrease the concentration.

[0024] These methods of emptying the stores are not without potential problems. 2+ The key feature of influx is that it is the Ca in the store that activates the channel. 2+ The subsequent decrease in cytoplasmic Ca 2+ However, ionomycin and SERCA pump blockers generally induce cytosolic Ca2+ accumulation as a result of store depletion. 2+ This causes an increase in Ca 2+ The increase in Ca 2+ Permeable to Ca 2+ One way to circumvent this problem is to use cytoplasmic Ca 2+ Ca-rich EGTA or BAPTA 2+ The use of the drug under conditions that are strongly buffered with a chelating agent.

[0025] Store-operated calcium entry A decrease in calcium concentration in intracellular calcium stores due to release of calcium from intracellular calcium stores such as the endoplasmic reticulum provides a signal for calcium to enter the cell from the extracellular medium. This calcium entry, which results in a sustained "plateau" increase in cytosolic calcium concentration, does not generally rely on voltage-dependent plasma membrane channels and does not involve activation of calcium channels by calcium. This calcium entry mechanism is referred to as capacitative calcium entry (CCE), calcium release-activated, store-operated, or depletion-operated calcium entry. Store-operated calcium entry can be recorded as an ionic current with distinctive properties. This current is called I SOC (store-operated current) or I CRAC (Calcium release activated current).

[0026] Electrophysiological analysis of store-operated or calcium release-activated currents reveals distinct biophysical properties of these currents (see, for example, Parekh and Penner (1997) Physiol. Rev. 77:901-930). For example, the current can be activated by depletion of intracellular calcium stores (e.g., by non-physiological activators such as thapsigargin, CPA, ionomycin, and BAPTA, as well as physiological activators such as IP3), can be selective for divalent cations such as calcium over monovalent ions in physiological solutions or conditions, can be affected by changes in cytoplasmic calcium levels, and can exhibit altered selectivity and conductance in the presence of low extracellular concentrations of divalent cations. This current can also be blocked or enhanced (depending on the concentration) by 2-APB, and can be potentiated by SKF96365 and Gd 3+ These currents can be blocked by other currents and overall can be described as calcium currents that are not strictly voltage-gated.

[0027] Patch clamp studies on mast cells and Jurkat leukemia T cells have demonstrated very low conductance and paired Ca 2+ We established the CRAC influx mechanism as an ion channel with unique biophysical characteristics, including high selectivity for cytosolic Ca. Furthermore, CRAC channels have been shown to fulfill stringent criteria for being store-operated, which means that they are capable of transporting cytosolic Ca. 2+ , or other messengers generated by PLC, but not Ca in the ER. 2+ Activation is achieved only by a decrease in .alpha. (Prakriya et al., In Molecular and Cellular Insights In Ion Channel Biology, edited by Robert Maue, pp. 121-140 (Elsevier Science, Amsterdam, 2004)).

[0028] Regulation of store-operated calcium entry by intracellular calcium stores Store-operated calcium entry is controlled by calcium levels in intracellular calcium stores, which can be characterized by their sensitivity to agents, which can be physiological or pharmacological, that activate calcium release from the stores or inhibit calcium uptake into the stores. Characterization of intracellular calcium stores has been studied in a variety of cells, and stores have been characterized as sensitive to a variety of agents, including, but not limited to, IP3, and compounds that affect the IP3 receptor, thapsigargin, ionomycin, and / or cyclic ADP-ribose (cADPR) (see, e.g., Berridge (1993) Nature 361:315-325; Churchill and Louis (1999) Am. J. Physiol. 276:C426-C434; Dargie et al. (1990) Cell Regul. 1:279-290; Gerasimenko et al. (1996) Cell 84:473-480; Gromoda et al. (1995) FEBS Lett. 360:303-306; Guse et al. (1999) Nature 398:70-73).

[0029] Accumulation of calcium within the endoplasmic reticulum and sarcoplasmic reticulum (SR; a specialized form of sarcoplasmic reticulum in striated muscle) storage organelles is accomplished by the endoplasmic-sarcoplasmic reticulum calcium ATPase (SERCA), commonly referred to as the calcium pump. During signal transduction (i.e., when endoplasmic reticulum channels are activated resulting in calcium release from the endoplasmic reticulum into the cytoplasm), endoplasmic reticulum calcium is replenished by the SERCA pump with cytoplasmic calcium that has entered the cell from the extracellular medium (Yu and Hinkle (2000) J. Biol. Chem. 275:23648-23653; Hofer et al. (1998) EMBO J. 17:1986-1995).

[0030] Calcium release channels associated with IP3 and ryanodine receptors result in the controlled release of calcium from the endoplasmic and sarcoplasmic reticulum into the cytoplasm, resulting in a transient increase in cytoplasmic calcium concentration. IP3 receptor-mediated calcium release is triggered by IP3, which is formed by the breakdown of plasma membrane phosphoinositides through the action of phospholipase C, which is activated by the binding of agonists to plasma membrane G protein-coupled receptors or tyrosine kinases. Ryanodine receptor-mediated calcium release is triggered by an increase in cytoplasmic calcium and is referred to as calcium-induced calcium release (CICR). The activity of ryanodine receptors (which have affinity for ryanodine and caffeine) can also be controlled by cyclic ADP-ribose.

[0031] Thus, calcium levels in the stores and in the cytoplasm fluctuate. For example, treatment of HeLa cells with histamine, an agonist of the PLC-bound histamine receptor, can reduce ER free calcium concentrations from a range of about 60-400 μM to about 1-50 μM (Miyawaki et al. (1997) Nature 388:882-887). Store-operated calcium entry is activated as the free calcium concentration in intracellular stores decreases. Thus, store calcium depletion, along with a concomitant increase in cytoplasmic calcium concentration, can control store-operated calcium entry into the cell.

[0032] Cytoplasmic calcium buffering Agonist activation of intracellular signaling processes can include, for example, a dramatic increase in the calcium permeability of the endoplasmic reticulum due to the opening of IP3 receptor channels, and a dramatic increase in the calcium permeability of the plasma membrane due to store-operated calcium influx. These increases in calcium permeability are associated with an increase in cytosolic calcium concentration that can be separated into two components: a "spike" of calcium release from the endoplasmic reticulum during IP3 receptor activation, and a plateau phase that is a sustained increase in calcium levels due to calcium influx from the extracellular medium into the cytoplasm. After stimulation, the resting intracellular free calcium concentration of about 100 nM can rise to 1 μM or more in the microdomains of the cell overall. Cells regulate these calcium signals using endogenous calcium buffers, including physiological buffering by organelles such as mitochondria, the endoplasmic reticulum, and the Golgi apparatus. Mitochondrial uptake of calcium through uniporters in the inner membrane is guided by a large, negative mitochondrial membrane potential, and accumulated calcium is slowly released through sodium-dependent and -independent exchangers, as well as, under some circumstances, the permeability transition pore (PTP). Thus, mitochondria can act as calcium buffers by taking up calcium during periods of cell activation and slowly releasing calcium later. Calcium uptake into the endoplasmic reticulum is controlled by sarcoplasmic and endoplasmic reticulum calcium ATPase (SERCA). Calcium uptake into the Golgi apparatus is mediated by P-type calcium transporting ATPase (PMR1 / ATP2C1). In addition, it has been demonstrated that a significant amount of calcium released upon IP3 receptor activation is extruded from the cell by the action of plasma membrane calcium ATPase. For example, plasma membrane calcium ATPase provides the primary mechanism of calcium clearance in human T cells and Jurkat cells, although sodium / calcium exchange also contributes to calcium clearance in human T cells. Within calcium storage organelles, calcium ions can bind to specialized calcium buffer proteins, such as calsequestrin, calreticulin, and calnexin.In addition, there are calcium buffering proteins in the cytosol that regulate calcium spikes and assist in the redistribution of calcium ions. Thus, proteins and other molecules involved in any of these and other mechanisms that can reduce cytosolic calcium levels are proteins that relate to, participate in, and / or result in cytosolic calcium buffering. Thus, cytosolic calcium buffering is a sustained calcium influx or Ca through SOC channels. 2+ During the bursts of release, cytoplasmic Ca 2+ Helps regulate levels of cytoplasmic Ca 2+ A large increase in levels or store repletion inactivates SOCE.

[0033] Downstream calcium influx-mediated events In addition to intracellular changes in calcium stores, store-operated calcium entry affects a number of events as a consequence of, or in addition to, store-operated changes. For example, Ca 2+Influx leads to the activation of numerous calmodulin-dependent enzymes, including the serine phosphatase calcineurin. Activation of calcineurin by increases in intracellular calcium leads to acute secretory processes such as mast cell degranulation. Activated mast cells release preformed granules containing enzymes such as histamine, heparin, TNFα, and P-hexosaminidase. Some cellular events, such as B-cell proliferation and T-cell proliferation, require sustained calcineurin signaling, which requires a sustained increase in intracellular calcium. Several transcription factors, including NFAT (nuclear factor of activated T cells), MEF2, and NFκB, are controlled by calcineurin. NFAT transcription factors play important roles in many cell types, including immune cells. In immune cells, NFAT mediates the transcription of numerous molecules, including cytokines, chemokines, and cell surface receptors. NFAT transcription elements have been found in the promoters of cytokines such as IL-2, IL-3, IL-4, IL-5, IL-8, and IL-13, as well as tumor necrosis factor alpha (TNFa), granulocyte colony-stimulating factor (G-CSF), and gamma-interferon (gamma-IFN).

[0034] The activity of NFAT protein is controlled by its phosphorylation level, and is controlled by both calcineurin and NFAT kinase. Activation of calcineurin by increasing intracellular calcium levels leads to dephosphorylation of NFAT and entry into the nucleus. Rephosphorylation of NFAT masks the nuclear localization sequence of NFAT, preventing it from entering the nucleus. NFAT is a sensitive indicator of intracellular free calcium levels, as it is highly dependent on calcineurin-mediated dephosphorylation for its localization and activity.

[0035] CRAC channels and the immune response CRAC channels are located in the plasma membrane and open in response to release of Ca2+ from endoplasmic reticulum stores. In immune cells, stimulation of cell surface receptors activates CRAC channels, resulting in Ca2+ influx and cytokine production. Cells of both the adaptive and innate immune systems (e.g., T cells, neutrophils, and macrophages) are known to be regulated by CRAC channels. CRAC channels also play a role in the activation of endothelial cells involved in the pathogenesis of ALL / ARDS. Normal pulmonary endothelium maintains a tight barrier between endothelial cells and the lung interstitium and alveolar space, thereby allowing gas exchange. In inflammatory conditions, stimulation of receptors on pulmonary endothelial cells leads to activation of Ca2+ influx through CRAC channels. Ca2+ influx leads to loss of barrier function resulting in leakage of protein-rich fluid into the alveoli, impaired gas exchange, and hypoxemia.

[0036] Stimulation of the T cell receptor results in the depletion of intracellular Ca2+ stores and the subsequent opening of CRAC (Ca2+ release-activated Ca2+) channels. Sustained increases in intracellular Ca2+ concentrations activate the calcineurin / NFAT (nuclear factor of activated T cells) pathway, setting in motion a transcriptional program of various cytokines. Orail and STIM1 are identified as the long-sought pore component of the CRAC channel and the endoplasmic reticulum (ER) Ca2+ sensor, respectively. STIM1 senses Ca2+ depletion in the ER after T cell receptor stimulation, translocates to the ER proximal to the plasma membrane (PM), and binds to and activates Orail. Human patients lacking Orail or STIM1 have severe combined immunodeficiency.

[0037] Calcium channel blockers Disclosed herein are several calcium channel inhibitors consistent with the methods, compositions, administration regimens, and compositions for use disclosed herein. In some embodiments, the calcium channel inhibitor comprises a SOC inhibitor. In some embodiments, the calcium channel inhibitor is a SOC inhibitor. In some embodiments, the SOC comprises a CRAC. In some embodiments, the SOC inhibitor comprises a CRAC inhibitor. In some embodiments, the calcium channel inhibitor is a CRAC inhibitor. In some embodiments, the calcium channel inhibitor inhibits a channel comprising a STIM1 protein. In some embodiments, the CRAC comprises an Orai1 protein. In some embodiments, the CRAC inhibitor comprises an Orai1 protein inhibitor. In some embodiments, the calcium channel inhibitor inhibits a channel comprising an Orai1 protein. In some embodiments, the CRAC comprises an Orai2 protein. In some embodiments, the CRAC inhibitor comprises an Orai2 protein inhibitor. In some embodiments, the calcium channel inhibitor inhibits a channel comprising an Orai2 protein.

[0038] In some embodiments, the compound is

[0039] [ka] or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the compound is selected from the list of compounds consisting of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects, the intracellular calcium signaling inhibitor is a compound of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

[0040] In some embodiments, the intracellular calcium signaling inhibitor is a CRACT inhibitor. In some aspects, the intracellular calcium signaling inhibitor is N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazole-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide, 3-fluoro- Fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazol-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazol-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6 -trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluoro 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl )-2-fluoro-6-methylbenzamide, 2,6-difluoro-N-(5-(2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)benzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, N-(5-(2,5-dimethylbenzo[d]oxazol-6-yl)thiazol-2-yl)-2,3,The compound is selected from among 6-trifluorobenzamide, N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(4-(2-((6-chloropyridin-3-yl)oxy)-4-methylthiazol-5-yl)phenyl)-2-fluorobenzamide, or a pharma- ceutically acceptable salt, pharma-ceutically acceptable solvate, or pharma-ceutically acceptable prodrug thereof. Each of these compounds is an example of a calcium channel inhibitor, a SOC inhibitor, or a CRAC inhibitor.

[0041] In some embodiments, the intracellular calcium signaling inhibitor is N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole ... -yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 3 -Fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazol-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methylisothiazol-4-yl)methyl)aniline, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)-2,6-difluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, 2,6-difluoro-N-(5-(2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)benzamide, N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(4-(2- ((6-chloropyridin-3-yl)oxy)-4-methylthiazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(2,5-dimethylbenzo[d]oxazol-6-yl)thiazol-2-yl)-2,3,6-trifluorobenzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharma- ceutically acceptable salt, pharma-ceutically acceptable solvate, or pharma-ceutically acceptable prodrug thereof. In some embodiments, the intracellular calcium signaling inhibitor is 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazole-2-yl)phenyl)benzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,In some embodiments, the intracellular calcium signaling inhibitor is N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharma- ceutically acceptable salt, pharma-ceutically acceptable solvate, or pharma-ceutically acceptable prodrug thereof. In some embodiments, the intracellular calcium signaling inhibitor is N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharma-ceutically acceptable salt, pharma-ceutically acceptable solvate, or pharma-ceutically acceptable prodrug thereof.

[0042] In some embodiments herein, a CRAC inhibitor is disclosed. In some embodiments, the CRAC inhibitor comprises SK&F 96365. In some embodiments, the CRAC inhibitor comprises econazole. In some embodiments, the CRAC inhibitor comprises L-651582. In some embodiments, the CRAC inhibitor comprises a carboxanilide compound. In some embodiments, the CRAC inhibitor comprises a biaryl carboxanilide compound. In some embodiments, the CRAC inhibitor comprises a heterocyclic carboxanilide compound. In some embodiments, the CRAC inhibitor comprises RP4010. In some embodiments, the CRAC inhibitor comprises Synta-66 (N-(2',5'-dimethoxy[1,1'-biphenyl]-4-yl)-3-fluoro-4-pyridinecarboxamide). In some embodiments, the CRAC inhibitor comprises ML-9 (1-(5-chloronaphthalene-1-sulfonyl)homopiperazine). In some embodiments, the CRAC inhibitor comprises capsaicin (8-methyl-N-vanillyl-(trans)-6-nonenamide). In some embodiments, the CRAC inhibitor comprises NPPB (5-nitro-2-(3-phenylpropylamino)-benzoic acid). In some embodiments, the CRAC inhibitor comprises DES (diethylstilbestrol). In some embodiments, the CRAC inhibitor comprises BEL (bromenol lactone, or E-6-(bromoethylene)tetrahydro-3-(1-naphthyl)-2H-pyran-2-one). In some embodiments, the CRAC inhibitor comprises carboxyamidotriazole (CAI). In some embodiments, the CRAC inhibitor comprises R02959 (2,6-difluoro-N-{5-[4-methyl-1-(5-methyl-thiazol-2-yl)-1,2,5,6-tetrahydro-pyridin-3-yl]-pyrazin-2-yl}-benzamide). In some embodiments, the CRAC inhibitor comprises Tanshinone IIA sulfonate. In some embodiments, the CRAC inhibitor comprises sodium Tanshinone IIA sulfonate. In some embodiments, the CRAC inhibitor comprises MRS1845. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0043] In some embodiments, a CRAC inhibitor is disclosed herein. In some embodiments, the CRAC inhibitor comprises a lanthanide. In some embodiments, the CRAC inhibitor comprises a lanthanide trivalent ion. In some embodiments, the CRAC inhibitor comprises La 3+ (lanthanum). In some embodiments, the CRAC inhibitor is Gd 3+ (gadolinium). Each of these compounds is also an example of a calcium channel blocker or SOC inhibitor.

[0044] In some embodiments herein, CRAC inhibitors are disclosed. In some embodiments, the CRAC inhibitor comprises imidazole. In some embodiments, the CRAC inhibitor comprises imidazole antifungal agent SKF-96365. In some embodiments, the CRAC inhibitor comprises econazole. In some embodiments, the CRAC inhibitor comprises miconazole. Each of these compounds is also an example of calcium channel inhibitor or SOC inhibitor.

[0045] In some embodiments herein, a CRAC inhibitor is disclosed. In some embodiments, the CRAC inhibitor comprises diphenyl boronate. In some embodiments, the CRAC inhibitor comprises 2-aminoethyl diphenyl borate (2-APB). In some embodiments, the CRAC inhibitor comprises DPB162-AE. In some embodiments, the CRAC inhibitor comprises DPB163-AE. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0046] In some embodiments, a CRAC inhibitor is disclosed herein. In some embodiments, the CRAC inhibitor comprises pyrazole. In some embodiments, the CRAC inhibitor comprises bis(trifluoromethyl)pyrazole. In some embodiments, the CRAC inhibitor comprises BTP1. In some embodiments, the CRAC inhibitor comprises BTP2. In some embodiments, the CRAC inhibitor comprises YM-58483. In some embodiments, the CRAC inhibitor comprises BTP3. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0047] In some embodiments herein, a CRAC inhibitor is disclosed. In some embodiments, the CRAC inhibitor comprises a Pyr compound. In some embodiments herein, a CRAC inhibitor is disclosed. In some embodiments, the CRAC inhibitor comprises N-(4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Pyr2 / BTP2 / YM58483). In some embodiments, the CRAC inhibitor comprises ethyl 1-(4-(2,3,3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Pyr3). In some embodiments, the CRAC inhibitor comprises N-(4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-3-fluoroisonicotinamide (Pyr6). In some embodiments, the CRAC inhibitor comprises N-(4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide (Pyr10). In some embodiments, the CRAC inhibitor comprises 2-aminoethoxydiphenylborate (2-APB). In some embodiments, the CRAC inhibitor comprises 2,2'-((((oxybis(methylene))bis(3,1-phenylene))bis(phenylboranediyl))bis(oxy))bis(ethan-1-amine) (DPB162-AE), 2,2'-((((oxybis(methylene))bis(4,1-phenylene))bis(phenylboranediyl))bis(oxy))bis(ethan-1-amine) (DPB163-AE). Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0048] In some embodiments herein, a CRAC inhibitor is disclosed. In some embodiments, the CRAC inhibitor comprises a GSK compound. In some embodiments, the CRAC inhibitor comprises GSK-5498A. In some embodiments, the CRAC inhibitor comprises GSK-5503A (2,6-difluoro-N-(1-(2-phenoxybenzyl)-1H-pyrazol-3-yl)benzamide). In some embodiments, the CRAC inhibitor comprises GSK-7975A (2,6-difluoro-N-(1-(4-hydroxy-2-(trifluoromethyl)benzyl)-1H-pyrazol-3-yl)benzamide). Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0049] In some embodiments herein, CRAC inhibitors are disclosed. In some embodiments, the CRAC inhibitor comprises polyunsaturated fatty acid (PUFA). In some embodiments, the CRAC inhibitor comprises 18-C PUFA. In some embodiments, the CRAC inhibitor comprises linoleic acid. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0050] In some embodiments herein, CRAC inhibitors are disclosed. In some embodiments, the CRAC inhibitor comprises 1-phenyl-3-(1-phenylethyl)urea. In some embodiments, the CRAC inhibitor comprises 1-phenyl-3-(1-phenylethyl)urea derivatives. In some embodiments, the CRAC inhibitor comprises 1-phenyl-3-(1-phenylethyl)urea derivatives, including compound 22. In some embodiments, the CRAC inhibitor comprises 1-phenyl-3-(1-phenylethyl)urea derivatives, including compound 23. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0051] In some embodiments herein, CRAC inhibitor is disclosed.In some embodiments, CRAC inhibitor comprises cholestatic bile acid.In some embodiments, CRAC inhibitor comprises taurolithocholic acid (TLCA; 2-[4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoylamino]ethanesulfonic acid). In some embodiments, the CRAC inhibitor comprises lithocholic acid (LCA; (4R)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid). In some embodiments, the CRAC inhibitor comprises cholic acid (CA; (R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid). In some embodiments, the CRAC inhibitor comprises taurocholic acid (TCA; 2-{[(3α,5β,7α,12α)-3,7,12-trihydroxy-24-oxocholan-24-yl]amino}ethanesulfonic acid). Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0052] In some embodiments herein, CRAC inhibitors are disclosed. In some embodiments, the CRAC inhibitor comprises FCC2121 (4-[3-(diphenylmethyl)-1,2,4-oxadiazol-5-yl]piperidinyl]piperidine. In some embodiments, the CRAC inhibitor comprises FCC2122 (3-(4-methyl-1,5-diphenyl-1H-pyrazol-3-yl)-2-phenylpropanoic acid. In some embodiments, the CRAC inhibitor comprises FC-2399 (2-(4-chloro-phenyl)-3-[1-(4-chloro-phenyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0053] In some embodiments herein, a CRAC inhibitor is disclosed. In some embodiments, the CRAC inhibitor is N-[1-({2-chloro-5-[(cyclopropylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide, N-{1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide, 2-bromo-N-{1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-6-fluorobenzamide, 2-chloro-N-{1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-6-fluorobenzamide, 2,6-dichloro-N-{1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-3-yl}benzamide, N-{1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-3,5-difluoro-4-pyridinecarboxamide, N-[1-({5-chloro-2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide amide, N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide, N-[1-({5-chloro-2-[(2-methylpropyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide, N-(1-{[2-bromo-5-(methyloxy)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide, N-(1-{[5-chloro-2-(methyloxy)phenyl]methyl}- 1H-pyrazol-3-yl)-2,6-difluorobenzamide, 2,6-difluoro-N-(1-{[2-(phenyloxy)phenyl]methyl}-1H-pyrazol-3-yl)benzamide, N-[1-({5-bromo-2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide, 2,6-difluoro-N-[1-({2-[(trifluoromethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]benzamide, 2,6-difluoro-N-(1-{[4-[(phenylmethyl)oxy]-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide, N-{1-[(2-bromo-6-chlorophenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide, 2,6-difluoro- / V-[1-({2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]benzamide, N / -[1-({2-chloro-5-[(2-methylpropyl)oxy]phenyl}methyl] ethyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide, N-(1-{[4-[(cyclopropylmethyl)oxy]-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide, 2,6-difluoro-N-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide, 2,6-difluoro-N-(1-{[4-methyl-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol- 3-yl)benzamide, N-(1-{[4-cyclopropyl-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide, 2,6-difluoro-N-{1-[(4-iodo-2-methylphenyl)methyl]-1H-pyrazol-3-yl}benzamide, N-(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide, 2-fluoro-N-(1-{[4-iodo-2-(trifluoro 2-chloro-N-(1-{[4-cyclopropyl-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide, N-(1-{[4-cyclopropyl-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2-fluorobenzamide, 2,6-difluoro-N-(1-{[5-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide, 2,6-difluoro-N-(1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide or 2,6-difluoro-N-(1-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0054] In some embodiments herein, CRAC inhibitors are disclosed.In some embodiments, CRAC inhibitors are N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-1H-benzo[d]imidazole-6-carboxamide, N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-1H-benzo[d][1,2,3]triazole-6-carboxamide, N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]quinoline-6-carboxamide, N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]quinoline-6-carboxamide, N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl) phenyl]quinoxaline-6-carboxamide, 2-(1H-benzo[d]imidazol-1-yl)-N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]acetamide, 2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]acetamide, N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-2-(1H-indol-3-yl)acetamide, N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-2-(1H-indol-3-yl)acetamide, Cyclopropyl-1H-pyrazol-1-yl)phenyl]-2-(imidazo[1,2-a]pyridin-2-yl)acetamide, N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-2-(quinolin-6-yl)acetamide, N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-2-(quinolin-6-yl)acetamide, 2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(4-(3,5-dicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl)acetamide, N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)-3-fluorophenyl]-2-(quinolin-6-yl)acetamide, N-[6-(3,5-dicyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]quinoline-6-carboxamide, N-[6-(3,5-dicyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]quinoxaline-6-carboxamide, 2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-[6-(3,5-Dicyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]acetamide, N-[6-(3,5-dicyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]-2-(quinolin-6-yl)acetamide, N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}quinoline-6-carboxamide, N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}quinoxaline-6-carboxamide Voxamide, 2-(1H-benzo[d]imidazol-1-yl)-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]acetamide, 2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide, 2-(2H-benzo[d][1,2,3]triazol-2-yl)-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide, (S)-2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-y])-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}propanamide, 2-(6-amino-9 H-purin-9-yl)-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide, N-(4-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide, N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(imidazo[1,2-a]pyridin-2-yl)acetamide, N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-(quinolin-6-yl)acetamide, N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-(quinolin-6-yl)propanamide, N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-fluorophenyl}-1H-benzo[d][1,2,3 ]triazole-6-carboxamide, 2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-fluorophenyl}acetamide, N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-1H-benzo[d][1,2,3]triazole-5-carboxamide, 2-(1H-benzo[d][1,2,3]triazol-1-yl)-N- {6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}acetamide, 2-(2H-benzo[d][1,2,3]triazol-2-yl)-N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}acetamide, N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-2-(quinolin-6-yl)acetamide, 2-(1H-benzo[d][1,2,3]triazol-2-yl)-N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}acetamide, and 1-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-3-(quinolin-6-yl)urea. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0055] In some embodiments herein, CRAC inhibitors are disclosed.In some embodiments, CRAC inhibitors are 4-[6-(2-chloro-6-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl]-3,N,N-trimethyl-benzenesulfonamide, 6-(2-chloro-phenyl)-2-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine, 4-[6-(2-chloro-phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-3-methyl-benzoic acid methyl ester, 4-(6-(2-chlorophenyl)-5H-pyrrolo[2,3-b] pyrazin-2-yl)-N,N,3-trimethylbenzenesulfonamide, 6-(2-chloro-6-fluorophenyl)-2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-5H-pyrrolo[2,3-b]pyrazine, 6-cyclohexyl-2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-5H-pyrrolo[2,3-b]pyrazine, or 4-(6-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-N,N,3-trimethylbenzenesulfonamide. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0056] In some embodiments herein, CRAC inhibitors are disclosed.In some embodiments, the CRAC inhibitors are 2,6-difluoro-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide, 2-fluoro-6-methyl-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin- 3-yl)benzamide, 5-(3-cyclopropyl-1-(5-(2,6-difluorobenzyl)amino)pyridin-2-yl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one, N-(6-(3-(difluoromethyl)-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide, 5-(1-(5-(2,6- difluorobenzyl)amino)pyridin-2-yl)-5-(fluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one, methyl 3-(1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate, methyl 3-(1-(5-(2-chloro-6-fluorobenzyl)amino)pyridin 2,6-difluoro-W-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide; 2-chloro-6-fluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-Oxadiazol-2-yl)-5-(trifluoromethyl)-\H-pyrazol-1-yl)pyridin-3-yl)benzamide, 2-fluoro-6-methyl- / v-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide, N-(6-(5-(difluoromethyl)-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl )pyridin-3-yl)-2,6-difluorobenzamide, 5-(1-(5((2,6-difluorobenzyl)amino)pyridin-2-yl)-5-(difluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one, 5-(1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-3-(difluoromethyl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one, N-(6-(3-(5,5-dimethyl-4-oxo-4,5- 2-chloro-N-(6-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-6-fluorobenzamide, 2,6-difluoro-N-(6-(1',4',4,-trimethyl-5'-oxo-5-(trifluoromethyl)-4',5'-dihydro-1H,1H'-[3 ,3'-bipyrazol]-1-yl)pyridin-3-yl)benzamide, 2-chloro-6-fluoro-N-(6-(1,4,4'-trimethyl-5'-oxo-5-(trifluoromethyl)-4',5,-dihydro-1H,1'H-[3,3'-bipyrazol]-1-yl)pyridin-3-yl)benzamide, 2-fluoro-6-methyl-N-(6-(1,4,4'-trimethyl-5'-oxo-5-(trifluoromethyl)-4',5'-dihydro-1H,1'H-[3,3'-bipyrazol]-1-yl)pyridin-3-yl)benzamide, 2,6-difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide, N-(6-(3-(4-acetyl-5,5-dimethyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide, N-(6-(3-(4,4-dimethyl-4, 5-dihydrooxazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide, 5-(1-(5-(2,6-difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one, 5-(1-(5-((2-chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazo 1'-(5-(2-chloro-6-fluorobenzyl)amino)pyridin-2-yl)-1,4,4-trimethyl-5'-(trifluoromethyl)-1H,1'H-[3,3'-bipyrazol]-5(4H)-one, 3-(1-( 5-(2,6-difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-1,2,4-oxadiazol-5(4H)-one, 1-(5-(1-(5-(2,6-difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimethyl-1,3,4-oxadiazol-3(2H)-yl)ethanone, N-(2,6-difluorobenzyl)-6-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine, N-(6-(5-cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide, N-(6-(3-cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2, 6-Difluorobenzamide, 2,6-difluoro-N-(6-(5-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide, 5-(1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-5-methyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one, (3-(I-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-5-(trifluorophenyl) (3-(1-(5-((2-chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol, methyl 3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol, methyl 3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol, 2,6-difluoro-N-(6-(3-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide, 3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxamide, 2,6-difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, 2-chloro-6-fluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, 2-fluoro-6-methyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide 2-Fluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, 2,3-difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, lysine-2-yl)benzamide, 2,4,5-trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, 2,3,4-trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, 2,4-difluoro 2-chloro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, 2,3-dimethyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, 2-chloro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-Oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, 2-methyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide, 4-ethyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1 / / -pyrazol-1-yl)pyridin-2-yl)benzamide, N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-13,4-oxadiazol, 5-(1-(6-((2,6-difluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one; 5-(1-(6-((2-chloro-6-fluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one; 5-(1-(6-((2-fluoro-6-methylbenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one; 5-(1-(6-(2-fluoro-6-methylbenzyl)amino)pyridim(p yridm)-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one, N-(2,6-difluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide, or N-(2-chloro-6-fluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide. Each of these compounds is also an example of a calcium channel inhibitor or SOC inhibitor.

[0057] In some embodiments herein, calcium channel inhibitor, SOC inhibitor or CRAC inhibitor is disclosed.In some embodiments, calcium channel inhibitor, SOC inhibitor or CRAC inhibitor comprises small molecule, such as small molecule that interferes with calcium channel activity, SOC channel activity or CRAC channel activity.In some embodiments, calcium channel inhibitor, SOC inhibitor or CRAC inhibitor comprises polypeptide, such as mutant form or non-functional form of calcium channel, SOC channel or CRAC channel component, that can interfere with calcium channel activity, SOC channel activity or CRAC channel activity.

[0058] Further forms of the compound The compounds described herein may exist as diastereomeric, enantiomeric, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography, or by diastereomeric and separation caused by recrystallization, chromatography, or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, which is incorporated herein by reference in this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0059] In some situations, compounds may exist as tautomers, and all tautomers are included within the formulae provided herein.

[0060] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, active metabolites of these compounds having the same type of activity are included within the scope of this disclosure. In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water and ethanol. Solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0061] In some embodiments, the compounds described herein may be prepared as prodrugs. A "prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because in some circumstances they may be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. A non-limiting example of a prodrug is a compound described herein that is administered as an ester ("prodrug") to facilitate transport across cell membranes where water solubility adversely affects mobility, but is subsequently metabolically hydrolyzed to the active entity, a carboxylic acid, once inside a cell where water solubility is beneficial. A further example of a prodrug may be a short chain peptide (polyamino acid) that is bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon administration in vivo, the prodrug is chemically converted to the biologically, pharma- ceutical, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharma- ceutical, or therapeutically active form of the compound.

[0062] To produce a prodrug, a pharma- ceutically active compound is modified such that the active compound is regenerated upon in vivo administration. Prodrugs can be designed to alter the metabolic stability or transport properties of a drug, to mask side effects or toxicity, to improve the taste of a drug, or to alter other properties or characteristics of a drug. In some embodiments, once a pharmacodynamic process and drug metabolism in vivo has been determined to determine the pharmacologic activity of a compound, a prodrug of the compound is designed (see, e.g., Nogrady (1985), Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 352-401; Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, 1985; Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Miller et al., J. Med. Chem. Vol. 46, no. 24, pp. 5097-5116, 2003; Aesop Cho, "Recent Advances in Oral Prodrug Discovery," Annual (See Reports in Medicinal Chemistry, Vol. 41, pp. 395-407, 2006).

[0063] Prodrug forms of the compounds described herein are included within the scope of the claims, where the prodrug is metabolized in vivo to produce a compound described herein. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0064] Prodrugs are often useful because in some circumstances they may be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs may be designed as reversible drug derivatives for use as modifiers to improve drug transport to site-specific tissues. In some embodiments, the design of prodrugs improves effective water solubility. See, for example, Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; and Edward B. Roche, Bioreversible See Carriers in Drug Design, American Pharmaceutical Association and Pergam on Press, 1987.

[0065] Sites on the aromatic ring portion of the compounds described herein are susceptible to a variety of metabolic reactions, and therefore incorporation of appropriate substituents on the aromatic ring structure, such as, by way of example only, halogens, may reduce, minimize, or eliminate this metabolic pathway.

[0066] The compounds described herein may be isotopically (e.g., with radioisotopes) or by other means, including, but not limited to, the use of chromophoric or fluorescent moieties, bioluminescent labels, photoactivated labels, or chemiluminescent labels.

[0067] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, but in which one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, and 36Cl, respectively. Certain isotopically labeled compounds described herein, such as those incorporating radioactive isotopes such as 3H and 14C, are useful for drug and / or substrate tissue distribution assays. In addition, substitution with isotopes such as deuterium, i.e., 2H, can provide certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo and reduced dosage requirements.

[0068] In additional or further embodiments, the compounds described herein, following administration to an organism in need thereof, are metabolized to produce metabolic products which are then used to provide a desired effect, including a desired therapeutic effect.

[0069] The compounds described herein can be formed as and / or used as pharmaceutically acceptable salts.Types of pharmaceutically acceptable salts include: (1) salts of the free base form of the compound with pharmaceutically acceptable inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octa-2- ... Examples of suitable salts include, but are not limited to, acid addition salts formed by reacting the parent compound with 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, or calcium), or an aluminum ion. Optionally, the compounds described herein may be combined with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, and the like. In other cases, the compounds described herein may form salts with amino acids, such as, but not limited to, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0070] It should be understood that the reference to a pharmaceutically acceptable salt includes the solvent addition form or its crystal form, specifically solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amount of solvent and can be formed during the crystallization process with a pharmaceutically acceptable solvent such as water or ethanol. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. Solvates of the compounds described herein can be conveniently prepared or formed during the process described herein. In addition, the compounds provided herein can optionally exist in solvated as well as unsolvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0071] In some embodiments, the compounds described herein are in various forms, including but not limited to amorphous, pulverized, injectable emulsion, and nanoparticle forms.Furthermore, the compounds described herein include crystalline forms, also known as polymorphs.Polymorphs include different crystal packing arrangements with the same elemental composition of a compound.Polymorphs usually have different X-ray diffraction patterns, melting points, densities, hardness, crystal shapes, optical properties, stability, and solubility.Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may cause a single crystalline form to predominate.

[0072] Screening and characterization of pharma- ceutically acceptable salts, polymorphs, and / or solvates may be accomplished using a variety of techniques, including but not limited to thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address thermochemical decomposition or thermophysical processes, including but not limited to polymorphic transitions, and such methods are used to analyze relationships between polymorphic forms, determine weight loss, find glass transition temperatures, or test excipient compatibility. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric-infrared analysis (TG / IR). X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers, as well as synchrotron sources. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UV-VIS, and NMR (liquid and solid state). Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy (in a gas or water vapor atmosphere) with EDX, IR microscopy, and Raman microscopy.

[0073] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0074] Synthesis of compounds In some embodiments, the synthesis of the compounds described herein is accomplished using means described in the chemical literature, using methods described herein, or a combination thereof. Additionally, solvents, temperatures, and other reaction conditions presented herein may be varied.

[0075] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0076] In further embodiments, the compounds described herein, and other related compounds having different substituents, can be prepared by any method, technique, or method described herein, in addition to the techniques and materials described herein, such as those described in, for example, Reagents for Organic Synthesis, Volumes 1-17 by Fieser and Fieser (John Wiley and Sons, 1991); Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals by Rodd (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Comprehensive Organic Transformations by Larock (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Advanced Organic Chemistry 4th Ed., Vols. A and B by Carey and Sundberg (Plenum 2000, 2001), and Protective Groups in Organic Synthesis 3rd Ed. by Green and Wuts, (Wiley The cleavage products are synthesized using art recognized techniques such as those described in (J. Chem. Soc. 1999), all of which are incorporated by reference for such disclosures.

[0077] PaO2 / FiO2 ratio The PaO2 / FiO2 (P / F) ratio can be a useful biomarker for patient selection in inflammatory lung injury diseases such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). A "normal" P / F ratio is considered to be about 300 or greater, while lower ratios indicate respiratory problems, e.g., a P / F ratio of 200-300 is mild respiratory insufficiency, 100-200 is moderate respiratory insufficiency, and less than 100 is severe respiratory insufficiency according to the Berlin criteria (https: / / www.mdcalc.com / berlin-criteria-acute-respiratory-distress-syndrome). Additionally, patient selection using the P / F ratio as a biomarker can help determine responders and non-responders to the methods described herein. Non-responders can be considered patients with a P / F ratio less than 100 after two doses of the therapeutic agent. In such cases, non-responders must receive a third dose, and up to six doses in total. Patients with a P / F ratio less than 100 had a mortality rate of up to 65%, whereas patients with a P / F ratio greater than 100 had a mortality rate of less than 10%.

[0078] In some embodiments, the present disclosure provides a method for treating acute lung injury (ALI), acute respiratory distress syndrome (ARDS), COVID-19 pneumonia, bacterial pneumonia, viral pneumonia, acute pancreatitis, or a combination thereof in a subject, comprising administering to the subject a therapeutically effective amount of an intracellular calcium signaling inhibitor, wherein the subject has a PaO2 / FiO2 (P / F) ratio of about 300 or less, and the subject has been administered at least two doses of the intracellular calcium signaling inhibitor. In some embodiments, the present disclosure provides a method for treating acute lung injury (ALI), acute respiratory distress syndrome (ARDS), COVID-19 pneumonia, bacterial pneumonia, viral pneumonia, acute pancreatitis, or a combination thereof in a subject, comprising administering to the subject a therapeutically effective amount of an intracellular calcium signaling inhibitor, wherein the subject has a PaO2 / FiO2 (P / F) ratio of about 150 or less, and the subject has been administered at least two doses of the intracellular calcium signaling inhibitor.

[0079] In some embodiments, the present disclosure provides a method for treating acute lung injury (ALI), acute respiratory distress syndrome (ARDS), COVID-19 pneumonia, bacterial pneumonia, viral pneumonia, acute pancreatitis, or a combination thereof in a subject, comprising administering to the subject a therapeutically effective amount of a corticosteroid and / or an immunosuppressant and an intracellular calcium signaling inhibitor, wherein the subject has a PaO2 / FiO2 (P / F) ratio of about 300 or less. In some embodiments, the present disclosure provides a method for treating acute lung injury (ALI), acute respiratory distress syndrome (ARDS), COVID-19 pneumonia, bacterial pneumonia, viral pneumonia, acute pancreatitis, or a combination thereof in a subject, comprising administering to the subject a therapeutically effective amount of a corticosteroid and / or an immunosuppressant and an intracellular calcium signaling inhibitor, wherein the subject has a PaO2 / FiO2 (P / F) ratio of about 150 or less.

[0080] The P / F ratio of a subject suitable for the methods of the present disclosure can be any suitable P / F ratio known to one of skill in the art. In some embodiments, the subject has a P / F ratio of about 200 or less. In some embodiments, the subject has a P / F ratio of about 150 or less. In some embodiments, the subject has a P / F ratio of about 100 or less. In some embodiments, the subject has a P / F ratio of about 50 to about 150. In some embodiments, the subject has a P / F ratio of about 50 to about 125. In some embodiments, the subject has a P / F ratio of about 50 to about 100. In some embodiments, the subject has a P / F ratio of about 75 to about 100. In some embodiments, the subject's P / F ratio is a P / F ratio of about 75 to about 150. In some embodiments, the subject exhibits modulation of the P / F ratio following administration of the intracellular calcium signaling inhibitor. In some embodiments, the subject exhibits an increase in the P / F ratio following administration of the intracellular calcium signaling inhibitor.

[0081] The subject's recovery rate after administration of the intracellular calcium signaling inhibitor can be any suitable value known to one of skill in the art. Furthermore, the subject's recovery rate is also applicable to combination therapy, where the intracellular calcium signaling inhibitor is administered with an effective amount of a corticosteroid or an immunosuppressant as described herein. In some embodiments, the subject's recovery rate is greater than about 35%. In some embodiments, the subject's recovery rate is greater than about 50%. In some embodiments, the subject's recovery rate is greater than about 75%. In some embodiments, the subject's recovery rate is greater than about 90%. In some embodiments, the subject's recovery rate is about 35% to about 100%. In some embodiments, the subject's recovery rate is about 35% to about 95%. In some embodiments, the subject's recovery rate is about 50% to about 100%. In some embodiments, the subject's recovery rate is about 50% to about 95%.

[0082] In some embodiments, the subject is further administered oxygen therapy.In some embodiments, the oxygen therapy is administered by rebreathing mask, Venturi mask, high flow nasal cannula (HFNC) or non-invasive ventilation (NIV).In some embodiments, the oxygen therapy is administered by high flow nasal cannula (HFNC) or non-invasive ventilation (NIV).

[0083] The administration of the intracellular calcium signaling inhibitor can be administered at any suitable dose that improves the subject's P / F ratio. In some embodiments, if the subject is administered two doses and has a P / F ratio of about 100 or less, the subject is considered a non-responder and must receive a third dose and at least a fourth, and possibly a fifth, or sixth dose of the intracellular calcium signaling inhibitor. In some embodiments, the subject has a P / F ratio of about 100 or less after receiving two doses of the intracellular calcium signaling inhibitor and receives at least three, four, five, or six doses in total. In some embodiments, the subject has a P / F ratio of about 100 or less after receiving two doses of the intracellular calcium signaling inhibitor and receives a third dose plus a total of four, five, or six doses. In some embodiments, the subject has a P / F ratio of about 100 or less after receiving two doses of the intracellular calcium signaling inhibitor and receives a third dose and at least a fourth, fifth, or sixth dose. In some embodiments, the intracellular calcium signaling inhibitor is administered at least three times. In some embodiments, the intracellular calcium signaling inhibitor is administered a total of 6 times, hi some embodiments, the intracellular calcium signaling inhibitor is administered at least 3, 4, 5, 6, 7, 8, 9, or 10 times.

[0084] In some embodiments, the second dose of the intracellular calcium signaling inhibitor is administered about 24 hours after the first dose. In some embodiments, the third dose of the intracellular calcium signaling inhibitor is administered about 48 hours after the first dose. In some embodiments, the concentration of the first dose is higher than the concentration of the second and third doses. In some embodiments, the concentration of the first dose is the same as the concentration of the second and third doses.

[0085] The intracellular calcium signaling inhibitor may be administered at any suitable concentration known to one of skill in the art. In some embodiments, the intracellular calcium signaling inhibitor is administered at a concentration of about 0.1 mg / kg to about 5 mg / kg. In some embodiments, the intracellular calcium signaling inhibitor is administered at a concentration of about 0.5 mg / kg to about 3 mg / kg. In some embodiments, the intracellular calcium signaling inhibitor is administered at a concentration of about 0.5 mg / kg to about 2.5 mg / kg. In some embodiments, the intracellular calcium signaling inhibitor is administered at a concentration of about 1 mg / kg to about 2.0 mg / kg. In some embodiments, the intracellular calcium signaling inhibitor is administered at a concentration of about 1.5 mg / kg to about 2.0 mg / kg. In some embodiments, the intracellular calcium signaling inhibitor is administered at a concentration of about 1.6 mg / kg to about 2.0 mg / kg. In some embodiments, the first administration is administered at a concentration of about 2.0 mg / kg, and the second and third administrations are administered at a concentration of about 1.6 mg / kg. In some embodiments, the concentration of the intracellular calcium signaling inhibitor is increased or decreased when the subject's P / F ratio is similar to the P / F ratio before administration.

[0086] Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS) ALI and ARDS are fatal and complex respiratory complications involving various pathogenic factors such as aspiration of gastric contents, microbial infection, sepsis, and trauma. Two major pathological features are present in ALI / ARDS: edema and neutrophil accumulation in lung tissue. Initial inflammatory stimuli disrupt the pulmonary endothelial and / or epithelial barrier and induce extravasation of protein-rich fluid, resulting in pulmonary edema. These stimuli also result in neutrophil infiltration into the interstitium and alveolar air spaces. The infiltrated neutrophils damage lung parenchymal cells by secreting elastase and reactive oxygen species, inducing further production of proinflammatory cytokines and activation of inflammatory cells. These physical and chemical tissue damages result in impaired air exchange and severe respiratory dysfunction.

[0087] Innate immune responses play a role in the pathophysiology of ALI / ARDS. Multiple immunological processes involving neutrophils, macrophages, and dendritic cells are involved in mediating tissue injury. Inflammatory insults arising locally from the lungs or systemically from extrapulmonary sites affect the bronchial epithelium, alveolar macrophages, and vascular endothelium, resulting in accumulation of protein-rich edema fluid in the alveoli and subsequent hypoxemia due to impaired gas exchange. Alveolar macrophages play a central role in orchestrating inflammation as well as in resolving ARDS. Upon stimulation, alveolar macrophages recruit neutrophils and circulating macrophages to sites of lung injury. These cells are involved in the anabolism of a variety of bioactive mediators that perpetuate the inflammatory response, including proteases, reactive oxygen species, eicosanoids, phospholipids, and cytokines. One crucial effect of these mediators is to damage or induce death of peripheral cells, particularly type 2 alveolar epithelial cells. These cells perform important functions by synthesizing and secreting pulmonary surfactant, an essential material that lines the lung inner surface and reduces alveolar surface tension. Type 2 cells are also actively involved in ion transport to control lung fluid. Taken together, these inflammatory events result in histological changes typical of the acute exudative phase that result in significant impairment of lung mechanics and gas exchange. During the early inflammatory and / or resolution phase of ARDS, alveolar macrophages also cooperate in a paracrine manner to interact with other cells, including epithelial cells, lymphocytes, and mesenchymal stem cells, that may result in an increased inflammatory response or accentuated tissue damage. A prolonged M1 (classically activated macrophages) or M2 (alternatively activated macrophages) phenotype is thought to be associated with non-healing chronic ARDS / ALI. ARDS / ALI is not a local pulmonary process but a systemic inflammatory disease with bidirectional involvement of the lung and other organ systems. Inflammatory cytokines such as IL-1β, TNF-α, IL-6, and IL-8 are elevated in both bronchoalveolar lavage fluid and circulating plasma in subjects with ARDS.

[0088] Bacterial and viral infections, such as coronavirus (COVID-19) infection, can lead to ALI / ARDS. During infection, circulating bacterial and / or viral products and endogenous cytokines (e.g., IL-2, IL-6) stimulate the endothelium, inducing a cascade of vascular activation, including increased expression of vascular adhesion molecules and a local increase in endothelial permeability.

[0089] In some embodiments, the ALI or ARDS is associated with a symptom or marker associated with ALI or ARDS. For example, ALI or ARDS can be associated with increased expression of Stim1, Orail, or PKCα, cellular Ca2+, or markers in a subject (e.g., in the lungs of a subject). 2+ Uptake or Ca 2+In some embodiments, the ALI or ARDS may be associated with increased levels, increased AMPK activation, increased ACC or PLC phosphorylation, downregulation of Na,K-ATPase, alveolar epithelial dysfunction, increased edema, increased lung wet / dry weight ratio, increased BALF protein levels, or increased endothelial permeability. In some embodiments, the ALI or ARDS comprises pulmonary inflammation and / or endothelial cell dysfunction in a subject, e.g., the lungs of a subject. In some embodiments, the inflammation is caused by or contributed to by endothelial cell dysfunction. In some embodiments, the ALI comprises pulmonary inflammation. In some embodiments, the ARDS comprises pulmonary inflammation. In some embodiments, the pulmonary inflammation is caused by or contributed to by pulmonary endothelial cell dysfunction. In some embodiments, the ALI comprises pulmonary endothelial cell dysfunction. In some embodiments, the ALI or ARDS comprises lung injury. In some embodiments, the ALI or ARDS comprises coughing. In some embodiments, the ALI or ARDS comprises dry coughing. In some embodiments, the ALI or ARDS comprises fever or high temperature. In some embodiments, the ALI or ARDS comprises shortness of breath. In some embodiments, the ALI or ARDS comprises a need for oxygen support. In some embodiments, the ALI or ARDS comprises a need for low flow oxygen. In some embodiments, the ALI or ARDS comprises a need for high flow oxygen. In some embodiments, the ALI or ARDS comprises a cytokine storm. In some embodiments, the ALI or ARDS comprises pulmonary endothelial injury. In some embodiments, the ALI or ARDS comprises CRAC channel hyperactivation. In some embodiments, the ALI or ARDS comprises increased intracellular calcium. In some embodiments, the ARDS comprises pulmonary endothelial cell dysfunction. In some embodiments, administration of a compound described herein, such as a CRAC inhibitor, may reduce, prevent, or reverse any of these symptoms.

[0090] In some embodiments, the ALI or ARDS comprises pneumonia. In some embodiments, the ALI comprises pneumonia. In some embodiments, the ARDS comprises pneumonia. In some embodiments, the pneumonia comprises a pneumonia stage such as consolidation, red hepatitis, gray hepatitis, or resolution. In some embodiments, the pneumonia comprises fluid accumulation in the lungs of the subject. In some embodiments, the pneumonia results in symptoms such as hypoxia or reduced blood oxygenation in the subject.

[0091] In some embodiments, the pneumonia comprises community-associated pneumonia. In some embodiments, the pneumonia comprises aspiration pneumonia. In some embodiments, the pneumonia is hospital-acquired pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia (VAP). In some embodiments, hospital-acquired pneumonia comprises VAP. In some embodiments, VAP is acquired in hospitalized and / or intubated patients. In some embodiments, the ALI is ventilator-induced. In some embodiments, ventilator-induced ALI is associated with increased endothelial permeability. In some embodiments, the ALI or ARDS is caused by sepsis, trauma, inhalation of toxic substances, blood transfusion, cocaine or other drug overdose, pancreatitis, or burns.

[0092] In some embodiments, the pneumonia comprises infection-associated pneumonia. In some embodiments, the ALI or ARDS comprises infection-associated pneumonia. In some embodiments, the pneumonia does not comprise infection-associated pneumonia. In some embodiments, the infection-associated pneumonia is hospital-acquired pneumonia.

[0093] In some embodiments, the pneumonia comprises viral pneumonia. In some embodiments, the ALI or ARDS comprises viral pneumonia. In some embodiments, the infection-associated pneumonia does not comprise viral pneumonia.

[0094] In some embodiments, the viral pneumonia comprises coronavirus pneumonia, influenza pneumonia, rhinovirus pneumonia, adenovirus pneumonia, or respiratory syncytial virus pneumonia. In some embodiments, the viral pneumonia comprises rhinovirus pneumonia. In some embodiments, the viral pneumonia comprises adenovirus pneumonia. In some embodiments, the viral pneumonia comprises respiratory syncytial virus pneumonia.

[0095] In some embodiments, the viral pneumonia comprises influenza pneumonia. In some embodiments, the influenza pneumonia comprises influenza A pneumonia. In some embodiments, the influenza pneumonia comprises influenza B pneumonia.

[0096] In some embodiments, the infection-associated pneumonia comprises bacterial pneumonia. In some embodiments, the bacterial pneumonia comprises Streptococcus pneumonia, Staphylococcus aureus pneumonia, Haemophilus influenzae pneumonia, Legionella pneumophilia pneumonia, or Methicillin resistant staphylococcus aureus (MRSA) pneumonia. In some embodiments, the bacterial pneumonia comprises Streptococcus pneumonia. In some embodiments, the bacterial pneumonia comprises Staphylococcus aureus pneumonia. In some embodiments, the bacterial pneumonia comprises Haemophilus influenzae pneumonia. In some embodiments, the bacterial pneumonia comprises Legionella pneumophilia pneumonia. In some embodiments, the bacterial pneumonia comprises Methicillin resistant staphylococcus aureus (MRSA) pneumonia. In some embodiments, the bacterial pneumonia comprises atypical pneumonia. An example of atypical pneumonia is pneumonia that does not respond to normal antibiotics. In some embodiments, the atypical pneumonia comprises Legionella pneumophila. In some embodiments, the atypical pneumonia comprises Chlamydophila pneumonia.

[0097] In some embodiments, the pneumonia comprises a parasite-associated pneumonia. In some embodiments, the infection-associated pneumonia comprises a Mycoplasma pneumonia. In some embodiments, the infection-associated pneumonia comprises a fungal pneumonia. In some embodiments, the fungal pneumonia comprises a Pneumocystis Jirovecii Pneumonia.

[0098] In some embodiments, the viral pneumonia comprises coronavirus pneumonia. In some embodiments, the ALI or ARDS comprises coronavirus pneumonia. In some embodiments, the viral pneumonia does not comprise coronavirus pneumonia. In some embodiments, the coronavirus pneumonia comprises COVID-19 pneumonia. In some embodiments, the ALI or ARDS comprises COVID-19 pneumonia. In some embodiments, the coronavirus pneumonia does not comprise COVID-19 pneumonia. In some embodiments, the coronavirus pneumonia comprises Severe Acute Respiratory Syndrome (SARS) pneumonia. In some embodiments, the coronavirus pneumonia comprises Middle East Respiratory Syndrome (MERS) pneumonia.

[0099] There is a solid rationale for treating severe COVID-19 pneumonia with CRAC inhibitors. Cytokines may lead to lung injury in COVID-19 patients. For example, IL-6 may play a role in leading to hyperactive inflammatory response in the lungs of patients with severe COVID-19 pneumonia. Elevated levels of IL-2, IL-17, and TNFα may also play a role in severe COVID-19 pneumonia.

[0100] CRAC channel inhibitors may have multiple MOAs beneficial for treating lung injury. For example, they may inhibit the release of multiple key cytokines: IL-2, IL-6, IL-17, TNFα. They may inhibit the respiratory burst caused by neutrophils and neutrophil infiltration. They may prevent activation of the pulmonary endothelium and destruction of the alveolar-capillary barrier.

[0101] Preclinical data support the use of CRAC inhibitors (e.g., N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, compound 1) for severe COVID-19 pneumonia. In vitro studies on human lymphocytes show that compound 1 inhibits the release of multiple cytokines. Animal models of acute pancreatitis (AP) and lung injury show that compound 1 and other CRAC channel inhibitors inhibit cytokine and neutrophil infiltration in lung tissue.

[0102] Clinical data support the use of CRAC inhibitors for severe COVID-19 pneumonia. Compound 1 injectable emulsion was safe for 365 days in healthy volunteers and for 90 days in patients with AP and concomitant SIRS plus hypoxemia. Treatment with Compound 1 resulted in a significant reduction in IL-6 levels in patients, with beneficial effects on respiratory dysfunction in patients.

[0103] In some embodiments, COVID-19 pneumonia includes severe pneumonia, or severe COVID-19 pneumonia. In some embodiments, ALI or ARDS includes severe COVID-19 pneumonia. In some embodiments, COVID-19 pneumonia includes severe or severe COVID-19 pneumonia. In some embodiments, COVID-19 pneumonia includes severe pneumonia, or severe COVID-19 pneumonia. In some embodiments, ALI or ARDS includes severe COVID-19 pneumonia. In some embodiments, COVID-19 pneumonia does not include severe COVID-19 pneumonia. In some embodiments, COVID-19 pneumonia does not include severe COVID-19 pneumonia.

[0104] In some embodiments, pneumonia includes severe or critical pneumonia. In some embodiments, ALI or ARDS includes severe pneumonia. An example of severe pneumonia includes pneumonia with impaired air exchange or respiratory function. An example of severe pneumonia includes the need for oxygen support, such as low-flow oxygen. In some embodiments, ALI or ARDS includes severe pneumonia. An example of severe pneumonia includes pneumonia with respiratory failure. An example of severe pneumonia includes the need for additional oxygen support or the need for high-flow oxygen. An example of severe pneumonia includes the need for mechanical ventilation or the need for intubation.

[0105] Therapeutic treatment of respiratory disorders such as ALI / ARDS Some embodiments herein disclose methods of administering the compositions described herein to a subject. Some embodiments relate to the use of the compositions described herein, such as administering the compositions to a subject.

[0106] Some embodiments relate to a method of treating a disorder in a subject in need of such treatment. Some embodiments relate to the use of a composition described herein in the treatment method. Some embodiments include administering a composition described herein to a subject having a disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject.

[0107] In some embodiments, the treatment comprises preventing, inhibiting, or reversing the disorder in the subject. Some embodiments relate to the use of the compositions described herein in a method of preventing, inhibiting, or reversing the disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder in a subject in need of such prevention, inhibition, or reversal. Some embodiments comprise administering a composition described herein to a subject having a disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subject.

[0108] Disclosed herein is a method for treating or preventing respiratory disorders. Some embodiments include treating respiratory disorders. Some embodiments include preventing respiratory disorders. Some embodiments include treating or alleviating symptoms of respiratory disorders. Some embodiments include administering a composition described herein, such as a pharmaceutical composition (e.g., a pharmaceutical composition comprising a calcium channel inhibitor, such as a CRAC inhibitor), to a subject in need of administering the composition. Some embodiments include identifying a subject as having or at risk of having a respiratory disorder.

[0109] In some embodiments, the respiratory disorder comprises an inflammatory disorder. In some embodiments, the inflammatory disorder comprises ALI or ARDS. In some embodiments, the respiratory disorder comprises ALI. In some embodiments, the respiratory disorder comprises ARDS. In some embodiments, the ALI or ARDS comprises pneumonia. In some embodiments, the respiratory disorder comprises pneumonia. The pneumonia may optionally be any pneumonia described herein. In some embodiments, the respiratory disorder is hospital-acquired. In some embodiments, the respiratory disorder is ventilator-associated or ventilator-induced.

[0110] In some embodiments, the respiratory disorder comprises an infection. In some embodiments, the infection comprises a viral infection. In some embodiments, the viral infection comprises a coronavirus infection. In some embodiments, the coronavirus infection comprises COVID-19. In some embodiments, the coronavirus infection comprises Severe Acute Respiratory Syndrome (SARS). In some embodiments, the infection comprises Middle East Respiratory Syndrome (MERS). In some embodiments, the viral infection comprises a rhinovirus infection. In some embodiments, the viral infection comprises an adenovirus infection. In some embodiments, the viral infection comprises a respiratory syncytial virus infection. In some embodiments, the viral infection comprises an influenza infection. In some embodiments, the influenza comprises influenza A. In some embodiments, the influenza comprises influenza B. In some embodiments, the influenza comprises influenza C. In some embodiments, the influenza comprises influenza D. In some embodiments, the influenza comprises a hemagglutinin subtype such as H1, H2, H3, H5, H6, H7, H9, or H10. In some embodiments, the influenza comprises a neuraminidase subtype, such as N1, N2, N6, N7, N8, or N9.

[0111] In some embodiments, the infection comprises a bacterial infection. In some embodiments, the bacterial infection comprises a Streptococcus infection. In some embodiments, the bacterial infection comprises a Staphylococcus aureus infection. In some embodiments, the bacterial infection comprises a Haemophilus influenzae infection. In some embodiments, the bacterial infection comprises a Legionella pneumophila infection. In some embodiments, the bacterial infection comprises a Methicillin-resistant Staphylococcus aureus (MRSA) infection. In some embodiments, the bacterial infection comprises a Legionella pneumophila. In some embodiments, the bacterial infection comprises a Chlamydophila infection.

[0112] In some embodiments, the infection comprises a parasitic infection. In some embodiments, the infection comprises a mycoplasma infection. In some embodiments, the infection comprises a fungal infection. In some embodiments, the fungal infection comprises a Pneumocystis jirovecii infection.

[0113] Disclosed herein are compositions and methods for treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) in a subject, the methods comprising administering to the subject a therapeutically effective amount of an intracellular calcium signaling inhibitor. Also disclosed herein are compositions and methods for preventing acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) in a subject at risk of developing ALI or ARDS, the methods comprising administering to the subject a therapeutically effective amount of an intracellular calcium signaling inhibitor.

[0114] The compositions and methods may be used in some embodiments to treat any ALI or ARDS, including, but not limited to, pneumonia, viral pneumonia, coronavirus pneumonia, COVID-19 pneumonia, severe COVID-19 pneumonia, such as COVID-19 with impaired air exchange or respiratory function, and / or severe COVID-19 pneumonia, such as COVID-19 with respiratory failure. The compositions and methods may be used to treat infectious diseases. The compositions and methods may be used to treat viral infections. The compositions and methods may be used to treat coronavirus infections. The compositions and methods may be used to treat COVID-19. In some embodiments, the compositions or methods described herein include a means for treating pneumonia, such as pneumonia described herein. The treatment may include administration of a compound or composition described herein to a subject. The subject may be identified as having a disease or disorder disclosed herein. The subject may be identified as at risk for having a disease or disorder disclosed herein.

[0115] The compositions and methods may be used in some embodiments to prevent any ALI or ARDS, including, but not limited to, pneumonia, viral pneumonia, coronavirus pneumonia, COVID-19 pneumonia, severe COVID-19 pneumonia, such as COVID-19 with impaired air exchange or respiratory function, and / or severe COVID-19 pneumonia, such as COVID-19 with respiratory failure. The compositions and methods may be used to prevent infectious diseases. The compositions and methods may be used to prevent viral infections. The compositions and methods may be used to prevent coronavirus infections. The compositions and methods may be used to prevent COVID-19. In some embodiments, the compositions or methods described herein include a means for preventing pneumonia, such as the pneumonias described herein. Prevention may include administration of a compound or composition described herein to a subject. The subject may be identified as having a disease or disorder disclosed herein. The subject may be identified as at risk for having a disease or disorder disclosed herein.

[0116] In some embodiments, the ALI or ARDS comprises pneumonia. In some embodiments, the pneumonia comprises severe pneumonia. In some embodiments, the pneumonia comprises severe pneumonia. In some embodiments, the pneumonia comprises viral pneumonia. In some embodiments, the viral pneumonia comprises viral pneumonia caused by a coronavirus, adenovirus, influenza virus, rhinovirus, or respiratory syncytial virus. In some embodiments, the viral pneumonia comprises viral pneumonia caused by a coronavirus. In some embodiments, the coronavirus is SARS-CoV, SARS-CoV-2, or MERS-CoV. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the pneumonia comprises severe or severe COVID-19 pneumonia.

[0117] The method of the present invention can further comprise identifying the subject as having respiratory insufficiency or respiratory disease.In some embodiments, the method further comprises identifying the subject as having ALI and / or ARDS.In some embodiments, the method further comprises identifying the subject as having ALI.In some embodiments, the method further comprises identifying the subject as having ARDS.

[0118] In some embodiments, the intracellular calcium signaling inhibitor is selected from the group consisting of an in vitro IC 50 In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration equal to, approximately equal to, or greater than the in vitro IC value determined for that compound. 50 1.5x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 11x, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 48x, 49x, 50x, 51x, 52x, 53x, 54x, 55x, 56x, 57x 5x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 70x, 71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 99x, 100x, or any non-integer multiple in the range of 1x-100x.

[0119] In some embodiments, the calcium signaling inhibitor is selected from the group consisting of an in vitro IC 50to achieve tissue level concentrations that are in the range of 1x-100x, 2x-80x, 3x-60x, 4x-50x, 5x-45x, 6x-44x, 7x-43x, 8x-43x, 9x-41x, or 10x-40x of the original concentration.

[0120] In some embodiments, the calcium signaling inhibitor is at least one of 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 36μM, 37μM, 38μM, 39μM, 4 0μM, 41μM, 42μM, 43μM, 44μM, 45μM, 46μM, 47μM, 48μM, 49μM, 50μM, 51μM, 52μM, 53μM, 54 μM, 55 μM, 56 μM, 57 μM, 58 μM, 59 μM, 60 μM, 61 μM, 62 μM, 63 μM, 64 μM, 65 μM, 66 μM, 67 μM, 68 μM M, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, 82μM , 83 μM, 84 μM, 85 μM, 86 μM, 87 μM, 88 μM, 89 μM, 90 μM, 91 μM, 92 μM, 93 μM, 94 μM, 95 μM, 96 μM, 97 μM, 98 μM, 99 μM, 100 μM, or any non-integer multiple ranging from 1 μM to 100 μM.

[0121] In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration of 1 μM to 100 μM, 2 μM to 90 μM, 3 μM to 80 μM, 4 μM to 70 μM, 5 μM to 60 μM, 6 μM to 50 μM, 7 μM to 40 μM, 8 μM to 30 μM, 9 μM to 20 μM, or 10 μM to 40 μM, or any integer or non-integer number within the aforementioned ranges.

[0122] In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration of 9.5 μM to 10.5 μM, 9 μM to 11 μM, 8 μM to 12 μM, 7 μM to 13 μM, 5 μM to 15 μM, 2 μM to 20 μM, or 1 μM to 50 μM, or any integer or non-integer number within the aforementioned ranges.

[0123] In one embodiment, a method of treating a patient with cytokine storm syndrome comprises administering to the patient a therapeutically effective amount of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In another embodiment, the patient is administered N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide intravenously. In a further embodiment, a method for inhibiting the release of multiple key cytokines comprises administering to the patient a therapeutically effective amount of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In a further embodiment, a method for inhibiting the release of IL-2, IL-6, IL-17, and / or TNFα comprises administering an effective amount of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In another embodiment, a method for inhibiting excessive or uncontrolled release of pro-inflammatory cytokines comprises administering an effective amount of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide.

[0124] N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide (Compound 1) is an example of a composition described herein that inhibits calcium release-activated calcium (CRAC) channels. Pharmaceutical compositions containing Compound 1 have been demonstrated to be safe and potentially effective for critically ill patients with acute pancreatitis. Its rapid onset may be beneficial in the acute phase. This may prevent the development of ARDS and / or reduce the need for mechanical ventilation in patients with severe COVID-19 pneumonia.

[0125] Compound 1 is a potent and selective small molecule inhibitor of CRAC channels, which are found in many cell types, including immune cells, where aberrant activation of these channels may play an important role in the pathobiology of acute and chronic inflammatory syndromes.

[0126] Due to the fast-acting nature of Compound 1, Compound 1 and other CRAC channel inhibitors may rapidly reduce the cytokine storm associated with COVID-19, stabilize the pulmonary endothelial capillary barrier, and prevent more severe lung damage. In patients with SARS-CoV-2 infection, morbidity and mortality may result from host immune responses. These responses may result in a cytokine storm, which later produces severe pneumonia and hypoxic respiratory failure, ARDS, death, or permanent loss of lung function in survivors.

[0127] Some embodiments of the methods described herein include obtaining a baseline measurement from the subject. For example, in some embodiments, the baseline measurement is obtained from the subject before treating the subject. Examples of baseline measurements include baseline protein measurements, baseline mRNA measurements, baseline pulmonary inflammation measurements, baseline pulmonary myeloperoxidase activity (e.g., neutrophil infiltration) measurements, baseline cytokine measurements (e.g., protein or mRNA levels of cytokines such as TNFα, IL-2, IL-6, IL-17, IFN-α, IFN-β, IFN-ω, and IFN-γ), baseline cytokine panel measurements, baseline procalcitonin measurements, baseline measurements of sustained systemic inflammatory response syndrome, baseline procalcitonin measurements, baseline endothelial cell Ca 2+ These include inflow measurements, baseline lung injury measurements, baseline endothelial pulmonary dysfunction measurements, baseline respiratory failure measurements (e.g., severity or duration), baseline need for supplemental oxygen or ventilatory support, baseline measurement of amount or duration of supplemental oxygen or ventilatory support, baseline lung fluid measurements, baseline PaO2 measurements, baseline FiO2 measurements, baseline PaO2 / FiO2 measurements, baseline SaO2 measurements, baseline ordinal scale measurements, baseline measurement of time to discharge, baseline temperature measurements, baseline fever measurements, or baseline heart rate measurements.

[0128] In some embodiments, the baseline measurement is obtained by performing an assay, such as an immunoassay, a colorimetric assay, or a fluorescent assay, on a sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, or a fluorescent assay. In some embodiments, the baseline measurement is obtained by PCR. In some embodiments, the PCR comprises RT-qPCR or RT-qPCR. For example, quantification or confirmation of viral particles, such as SARS-Cov-2 nucleic acid, may be obtained using an RT-PCR assay of a nasal swab, a throat swab, or an airway aspirate.

[0129] In some embodiments, the baseline measurements are obtained directly in or on the subject. In some embodiments, the baseline measurements are obtained using a nasal cannula. In some embodiments, the baseline measurements are obtained using pulse oximetry. In some embodiments, the baseline measurements are obtained using a thermometer. In some embodiments, the baseline measurements are obtained by performing a visual inspection of the subject. In some embodiments, the baseline measurements are obtained using a medical imaging device.

[0130] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, a baseline measurement is obtained from the subject prior to administration of a composition described herein. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject prior to administration of a composition to the subject.

[0131] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the fluid sample is a bronchoalveolar lavage (BAL) sample. In some embodiments, the sample comprises a nasal sample. In some embodiments, the sample comprises a throat sample. In some embodiments, the sample comprises a swab (e.g., a nasal swab or a throat swab). In some embodiments, the sample comprises an aspirate. In some embodiments, the sample comprises an airway sample (e.g., an airway aspirate). In some embodiments, the sample comprises or consists of a blood, plasma, or serum sample. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a serum sample. In some embodiments, the sample comprises tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the sample comprises or consists of lung tissue. In some embodiments, the sample comprises or consists of one or more lung cells. The lung cells may be epithelial cells or endothelial cells. In some embodiments, the sample comprises or consists of one or more endothelial cells, such as lung endothelial cells. In some embodiments, the sample comprises or consists of one or more epithelial cells, such as alveolar epithelial cells.

[0132] In some embodiments, the composition, or administration of the composition, affects a measurement such as a protein measurement, an mRNA measurement, a pulmonary inflammation measurement, a pulmonary myeloperoxidase activity (e.g., neutrophil infiltration) measurement, a cytokine measurement (e.g., protein or mRNA levels of cytokines such as TNFα, IL-6, IL-17, other cytokines), a cytokine panel measurement, a procalcitonin measurement, a sustained systemic inflammatory response syndrome measurement, a procalcitonin measurement, an endothelial cell Ca2+ influx measurement, a lung injury measurement, an endothelial pulmonary dysfunction measurement, a respiratory failure measurement (e.g., severity or duration), a need for supplemental oxygen or ventilatory support, a measurement of the amount or duration of supplemental oxygen or ventilatory support, a lung fluid measurement, a PaO2 measurement, a FiO2 measurement, a PaO2 / FiO2 measurement, a SaO2 measurement, a time to discharge measurement, an ordinal scale measurement, a temperature measurement, a fever measurement, or a heart rate measurement. In some embodiments, the composition improves a measurement compared to a baseline measurement. In some embodiments, another measure is improved, such as a symptom or marker associated with the disorder (e.g., acute respiratory distress syndrome (ARDS), as discussed in the section on acute lung injury (ALI) and its severe manifestations). In some embodiments, the composition reduces the measure compared to a baseline measure. In some embodiments, the composition increases the measure compared to a baseline measure.

[0133] Some embodiments of the methods described herein include obtaining a measurement from a subject. For example, the measurement may be obtained from the subject after the subject has been treated. In some embodiments, the CRAC inhibitor is administered to the subject at 0 hours (at the beginning of the first infusion of the CRAC inhibitor) for the first dose, and subsequent different doses may be administered at 0 hours, 24 hours, and 48 hours. In some embodiments, subsequent doses of the CRAC inhibitor may be administered at 0 hours, 72 hours, and later. In some embodiments, the measurement is obtained in a sample collected at the aforementioned 24 hours. In some embodiments, the measurement is obtained in a sample collected at the aforementioned 48 hours. In some embodiments, the measurement is obtained in a sample collected at the aforementioned 72 hours. In some embodiments, the measurement is obtained in a second sample (such as a blood, plasma, serum, or lung sample) as described herein obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement is an indication that the disorder has been treated. In some embodiments, the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained non-invasively, such as by using an imaging device.

[0134] In some embodiments, after administration of the composition (e.g., an intracellular calcium signaling inhibitor or CRAC inhibitor), the subject shows improvement (e.g., increase in value) in intraoral scales, including intraoral pneumonia scales, such as: 1. death, 2. hospitalization, invasive mechanical ventilation or use of ECMO, 3. hospitalization, non-invasive ventilation or high-flow oxygen device, 4. hospitalization, requiring supplemental oxygen, 5. hospitalization, no supplemental oxygen required - continued treatment required (COVID-19 related or otherwise), 6. hospitalization, no supplemental oxygen required - no continued treatment required (except for investigational drug administration as per protocol), 7. no hospitalization.

[0135] In some embodiments, administering the composition (e.g., an intracellular calcium signaling inhibitor or CRAC inhibitor) to a subject reduces a measure of the subject's length of stay. In some embodiments, the length of stay measure is the amount of time in the hospital. In some embodiments, the length of stay measure is a measure of time to discharge. In some embodiments, administering the composition reduces the number of hospitalizations.

[0136] In some embodiments, administering the composition (e.g., an intracellular calcium signaling inhibitor, or CRAC inhibitor) to a subject improves the oxygen tension (PaO2) value in the subject. For example, the PaO2 value can be increased by administering the composition. In some embodiments, administering the composition to a subject improves the ratio of oxygen tension to fraction of inspired oxygen (PaO2 / FiO2) in the subject. For example, the PaO2 / FiO2 can be increased by administering the composition.

[0137] In some embodiments, administration of the composition to a subject prevents, reduces, or eliminates the need for supplemental oxygen or ventilatory support to the subject. In some embodiments, administration of the composition prevents the need for oxygen support. In some embodiments, administration of the composition reduces the need for oxygen support. In some embodiments, administration of the composition eliminates the need for oxygen support. In some embodiments, administration of the composition prevents the need for ventilatory support. In some embodiments, administration of the composition reduces the need for ventilatory support. In some embodiments, administration of the composition eliminates the need for ventilatory support. In some embodiments, administration of the composition reduces the amount of supplemental oxygen support. In some embodiments, administration of the composition reduces the duration of supplemental oxygen support. In some embodiments, administration of the composition reduces the amount of ventilatory support. In some embodiments, administration of the composition reduces the duration of ventilatory support.

[0138] In some embodiments herein, a method of treatment is disclosed that may include administering a compound disclosed herein to a subject. Some embodiments further include administering a respiratory treatment to the subject. In some embodiments, the respiratory treatment includes respiratory assistance. In some embodiments, the respiratory assistance includes intubation, such as endotracheal intubation, ventilation, such as mechanical ventilation or non-invasive ventilation, or oxygen support. In some embodiments, the subject is already receiving a respiratory treatment, such as respiratory assistance, before administration of the composition or before starting treatment with the composition. In some embodiments, the respiratory treatment and the composition are administered simultaneously. In some embodiments, the respiratory treatment and the treatment with the composition overlap.

[0139] In some embodiments, a calcium channel inhibitor (e.g., Auxora) is administered at a dosage of about 0.5 mg / kg, 1.0 mg / kg, 1.5 mg / kg, 2 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 225 mg / kg, 250 mg / kg, or any number between any two of the foregoing values.

[0140] Coadministration with Compounds to Treat ALI / ARDS Disclosed herein are compositions and administration regimens for the combined administration of a calcium channel inhibitor and at least one compound for treating ALI or ARDS. In some embodiments, the administration regimen comprises administering a compound for treating ALI or ARDS to a subject and administering an intracellular calcium signaling inhibitor. In some embodiments, the administration regimen comprises administering a corticosteroid or an immunosuppressant and an intracellular calcium signaling inhibitor to a subject. In some embodiments, a therapeutically effective amount of the corticosteroid and / or the immunosuppressant and the intracellular calcium signaling inhibitor are administered at different times. In some embodiments, a therapeutically effective amount of the corticosteroid and / or the immunosuppressant and the intracellular calcium signaling inhibitor are administered simultaneously.

[0141] In some embodiments, the corticosteroid is a glucocorticoid or a mineralocorticoid. In some embodiments, the corticosteroid is aldosterone, corticosterone, cortisol, cortisone, pregnenolone, progesterone, flugestone, fluorometholone, medrysone, prevesilone acetate, chloroprednisone, cloprednol, difluprednate, fludrocorisomone, fluocinolone, fluoperolone, loteprednol, methylprednisolone, prednicarbate, prednisolone, prednisone, tixocortol, triamcinolone, alclometasone, beclomethasone, betamethasone, clobetasol, clobetasone, clocortolone, desoximetolone, cyclosporine ... The drug is selected from the group consisting of fluocortolone, fluclorone, flumethasone, fluocortin, fluocortolone, fluprednidene, fluticasone, fluticasone furoate, halometasone, medoprednisone, mometasone, mometasone furoate, paramethasone, prednylidene, rimexolone, urobetasol, amcinonide, budesonide, ciclesonide, deflazacort, desonide, formocortal, fluclorone acetonide, fludroxycortide, flunisolide, fluocinolone acetonide, fluocinonide, halcinonide, and triamcinolone acetonide. In some embodiments, the corticosteroid is cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone, fludrocortisone acetate, deoxycorticosterone, deoxycorticosterone acetate, aldosterone, beclomethasone, or progesterone.

[0142] In some embodiments, the immunosuppressant is cyclosporine, tacrolimus, sirolimus, everolimus, azathioprine, cyclophosphamide, methotrexate, mycophenolate, leflunomide, abatacept, adalimumab, alemtuzumab, anakinra, basilizimab, belimumab, bevacizumab, brodalumab, canakinumab, certolizumab, cetuximab, In some embodiments, the immunosuppressant is not a medicament for use with the immunosuppressant IL-6 inhibitor, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, IL-49 ...0, IL-41, IL-42, IL-43, IL-44, IL-45, IL-45, IL-46, IL-47, IL-48, IL-49, IL-49, IL-49, IL-49, IL-49, IL-49, IL-49, IL-40, IL-41,

[0143] In some embodiments, the compound is selected from the list consisting of prostaglandin inhibitors, complement inhibitors, beta-agonists, beta-2 agonists, granulocyte macrophage colony stimulating factor, corticosteroids, N-acetylcysteine, statins, glucagon-like peptide-1 (7-36) amide (GLP-1), triggering receptor expressed on myeloid cells (TREM1) blocking peptide, 17-allylamino-17-demethoxygeldanamycin (17-AAG), antibodies against tumor necrosis factor (TNF), recombinant interleukin (IL)-1 receptor antagonists, cisatracurium besylate, and angiotensin-converting enzyme (ACE) inhibitors. In some embodiments, the compound comprises an antiviral compound. In some embodiments, the antiviral compound is an anticoronavirus compound. In some embodiments, the anticoronavirus compound comprises remdesivir. Examples of antiviral compounds include antiretroviral compounds, protease inhibitors, nucleoside reverse transcriptase inhibitors, reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors, maturation inhibitors, anti-influenza compounds, peramivir, zanamivir, oseltamivir, baloxavir, marboxil, and pharmaceutically acceptable salts thereof. In some embodiments, the compound comprises an antibiotic. In some embodiments, the compound comprises an antimalarial. In some embodiments, the compound comprises hydroxychloroquine. In some embodiments, the compound comprises chloroquine.

[0144] In some embodiments, the intracellular calcium signaling inhibitor is a SOC inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC inhibitor. Exemplary CRAC inhibitors include:

[0145] [ka] Exemplary CRAC inhibitors include N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide having the structure: Exemplary CRAC inhibitors include GSK-7975A. Exemplary CRAC inhibitors include BTP2. Exemplary CRAC inhibitors include 2,6-difluoro-N-(1-(4-hydroxy-2-(trifluoromethyl)benzyl)-1H-pyrazol-3-yl)benzamide.

[0146] In some embodiments, the dosing regimen includes administration of a calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, and a compound for treating ALI / ARDS. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, is administered on the same day as the compound for treating ALI / ARDS on pulmonary activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, is administered in the same week as the compound for treating ALI / ARDS. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, is administered simultaneously with each administration of the compound for treating ALI / ARDS. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, is administered in a dosing regimen pattern that is independent of the dosing pattern of the compound for treating ALI / ARDS. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, is administered through the same delivery route, such as oral or intravenous, as the compound for treating ALI / ARDS.In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, is administered through a different delivery route than the compound for treating ALI / ARDS. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, is administered to an individual receiving the compound for treating ALI / ARDS only after the individual shows at least one sign of an effect of the drug on pulmonary activity. In some embodiments, a calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, is administered to an individual receiving a compound for treating ALI / ARDS in or in the absence of evidence of any indication of an effect of the compound on pulmonary activity.

[0147] In some embodiments, a calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide and BTP2, is administered as a composition with a compound for treating ALI / ARDS. Accordingly, some embodiments disclosed herein relate to a composition comprising an intracellular calcium signaling inhibitor and at least one compound for treating ALI / ARDS. In some embodiments, the at least one drug is selected from the list consisting of prostaglandin inhibitors, complement inhibitors, beta-agonists, beta-2 agonists, granulocyte-macrophage colony-stimulating factor, corticosteroids, N-acetylcysteine, statins, glucagon-like peptide-1 (7-36) amide (GLP-1), triggering receptor expressed on myeloid cells (TREM1) blocking peptide, 17-allylamino-17-demethoxygeldanamycin (17-AAG), antibodies against tumor necrosis factor (TNF), recombinant interleukin (IL)-1 receptor antagonists, cisatracurium besylate, and angiotensin-converting enzyme (ACE) inhibitors.

[0148] In some embodiments, the intracellular calcium signaling inhibitor is selected from the group consisting of an in vitro IC 50 In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration equal to, approximately equal to, or greater than the in vitro IC value determined for that compound. 501.5x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 11x, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 48x, 49x, 50x, 51x, 52x, 53x, 54x, 55x, 56x, 57x 5x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 70x, 71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 99x, 100x, or any non-integer multiple in the range of 1x-100x.

[0149] In some embodiments, the calcium signaling inhibitor is selected from the group consisting of an in vitro IC 50 to achieve tissue level concentrations that are in the range of 1x-100x, 2x-80x, 3x-60x, 4x-50x, 5x-45x, 6x-44x, 7x-43x, 8x-43x, 9x-41x, or 10x-40x of the original concentration.

[0150] In some embodiments, the calcium signaling inhibitor is at least one of 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 36μM, 37μM, 38μM, 39μM, 4 0μM, 41μM, 42μM, 43μM, 44μM, 45μM, 46μM, 47μM, 48μM, 49μM, 50μM, 51μM, 52μM, 53μM, 54 μM, 55 μM, 56 μM, 57 μM, 58 μM, 59 μM, 60 μM, 61 μM, 62 μM, 63 μM, 64 μM, 65 μM, 66 μM, 67 μM, 68 μM M, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, 82μM , 83 μM, 84 μM, 85 μM, 86 μM, 87 μM, 88 μM, 89 μM, 90 μM, 91 μM, 92 μM, 93 μM, 94 μM, 95 μM, 96 μM, 97 μM, 98 μM, 99 μM, 100 μM, or any non-integer multiple ranging from 1 μM to 100 μM.

[0151] In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration of 1 μM to 100 μM, 2 μM to 90 μM, 3 μM to 80 μM, 4 μM to 70 μM, 5 μM to 60 μM, 6 μM to 50 μM, 7 μM to 40 μM, 8 μM to 30 μM, 9 μM to 20 μM, or 10 μM to 40 μM, or any integer or non-integer number within the aforementioned ranges.

[0152] In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration of 9.5 μM to 10.5 μM, 9 μM to 11 μM, 8 μM to 12 μM, 7 μM to 13 μM, 5 μM to 15 μM, 2 μM to 20 μM, or 1 μM to 50 μM, or any integer or non-integer number within the aforementioned ranges.

[0153] Pharmaceutical Compositions This specification may provide a pharmaceutical composition comprising at least one of the calcium signaling inhibitors described herein.Optionally, this pharmaceutical composition comprises at least one of the calcium signaling inhibitors and at least one of the compounds for treating ALI and / or ARDS disclosed herein.

[0154] The pharmaceutical compositions provided herein can be introduced as oral forms, transdermal forms, oily formulations, edibles, food matrices, aqueous dispersions, emulsions, injectable emulsions, solutions, suspensions, elixirs, gels, syrups, aerosols, mists, powders, capsules, tablets, nanoparticles, nanoparticle suspensions, nanoparticle emulsions, lozenges, lotions, pastes, formulated sticks, balms, creams, and / or ointments.

[0155] In some embodiments, the pharmaceutical composition further comprises at least one of an excipient, a solubilizer, a surfactant, a disintegrant, and a buffer. In some embodiments, the pharmaceutical composition does not comprise a pharma- ceutically acceptable excipient. The term "pharma-ceutically acceptable excipient" as used herein means one or more compatible solid or encapsulating substances suitable for administration to a subject. The term "compatibility" as used herein means that the components of the composition are capable of mixing with the subject compound and with each other such that there is no interaction that would substantially reduce the pharmaceutical efficacy of the composition under normal conditions of use. In some embodiments, the pharma-ceutically acceptable excipient is preferably of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the animal, preferably a mammal, to be treated.

[0156] Some examples of substances that can function as pharma- ceutically acceptable excipients include amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In some embodiments, the amino acid is arginine. In some embodiments, the amino acid is selected from the group consisting of L-arginine; monosaccharides such as glucose (dextrose), arabinose, mannitol, fructose (levulose), and galactose; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; solid lubricants, such as talc, stearic acid, magnesium stearate, and sodium stearyl fumarate; polyols, such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; emulsifiers, such as polysorbates; wetting agents, such as sodium lauryl sulfate, Tween®, Span, alkyl sulfates, and alkyl ethoxylate sulfates; cationic surfactants such as trimide, benzalkonium chloride, and cetylpyridinium chloride; diluents such as calcium carbonate, microcrystalline cellulose, calcium phosphate, starch, pregelatinized starch, sodium carbonate, mannitol, and lactose; binders such as starch (corn starch and potato starch), gelatin, sucrose hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC); disintegrants such as starch and alginic acid; and super-disintegrants such as ac-di-sol, croscarmellose sodium, sodium starch glycolate, and crospovidone.

[0157] glidants such as silicon dioxide; colorants such as the FD&C dyes; sweeteners and flavorings such as aspartame, saccharin, menthol, peppermint, and fruit flavors; preservatives such as benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, parabens, sodium benzoate; isotonicity adjusters such as sodium chloride, potassium chloride, mannitol, and glycerin; antioxidants such as sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA; pH adjusters such as NaOH, sodium carbonate, sodium acetate, HCl, and citric acid; cryoprotectants such as sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, dextran, and surfactants such as sodium lauryl sulfate. For example, cationic surfactants such as cetrimide (including tetradecyltrimethylammonium bromide with dodecyl and hexadecyl compounds), benzalkonium chloride, and cetylpyridinium chloride. Some examples of anionic surfactants are alkyl sulfates, alkyl ethoxylate sulfates, soaps, carboxylate ions, sulfate ions, and sulfonate ions. Some examples of nonionic surfactants are polyoxyethylene derivatives, polyoxypropylene derivatives, polyol derivatives, polyol esters, polyoxyethylene esters, poloxamers, glycols, glycerol esters, sorbitan derivatives, polyethylene glycols (such as PEG-40, PEG-50, or PEG-55), and esters of fatty alcohols; organic materials such as carbohydrates, modified carbohydrates, lactose (including α-lactose, spray-dried lactose monohydrate, or anhydrous lactose), starch, pregelatinized starch, sucrose, mannitol, sorbital, cellulose (including powdered cellulose and microcrystalline cellulose); inorganic materials such as calcium phosphate (including anhydrous dibasic calcium phosphate, dibasic calcium phosphate, or tribasic calcium phosphate); co-processed diluents; compression aids; and anti-adherents such as silicon dioxide and talc.

[0158] In some embodiments, the pharmaceutical compositions described herein are provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing at least one of the calcium signaling inhibitors and / or at least one of the compounds for treating ALI and / or ARDS in an amount suitable for administration in a single dose to a subject, in accordance with the principles of good medical practice. However, the preparation of a single dosage form or unit dosage form does not suggest that the dosage form is administered once per day or once during the course of treatment. Such dosage forms are contemplated to be administered once, twice, three times, or more per day, and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours) or as a continuous infusion, and may be administered more than once during the course of treatment, although single administration is not specifically excluded.

[0159] Specific Terms Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood to belong to the claimed subject matter. In the event that there are multiple definitions for terms in this specification, the definitions in this section shall prevail. When referring to a URL or other such identifier or address, it is understood that such identifiers may change and specific information on the Internet may come and go, but equivalent information may be found by Internet search. Reference thereto evidences the availability and public dissemination of such information.

[0160] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit all claimed subject matter. In this application, the use of the singular includes the plural unless otherwise specified. It should be noted that as used in this specification and the appended claims, the singular forms "a", "an" and "the" include the plural unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless otherwise specified. Furthermore, the use of the term "including" as well as other forms such as "include", "includes" and "included" are not limiting.

[0161] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0162] Definitions of standard chemical terms may be found in references including, but not limited to, "Advanced Organic Chemistry 4th Ed" Vols. A (2000) and B (2001) by Carey and Sundberg, Plenum Press, New York. Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used.

[0163] Unless specific definitions are provided, the nomenclature adopted in connection with analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry described herein, as well as the experimental procedures and techniques thereof, are those recognized in the art. Standard techniques for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and patient treatment can be used. Standard techniques for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection) can be used. Reactions and purification techniques can be performed, for example, using kits according to manufacturer's specifications, or as commonly accomplished in the art or described herein. The techniques and procedures described above can generally be performed by conventional methods and as described in various general and more specific references cited and discussed throughout this specification.

[0164] It is to be understood that the methods and compositions described herein are not limited to the specific methodologies, protocols, cell lines, constructs, and reagents described herein, and therefore may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0165] The terms "kit" and "article of manufacture" are used synonymously.

[0166] The term "subject" or "patient" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the following mammalian classes: humans, non-human primates such as chimpanzees, other apes, and monkey species; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0167] "Treat", "treating" or "treatment" as used herein includes alleviating, reducing or relieving symptoms of a disease or condition, preventing additional symptoms, relieving or preventing the underlying cause of a condition, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving a co-morbid condition caused by a disease or condition, or prophylactically and / or therapeutically arresting symptoms of a disease or condition. As used herein, the term "target protein" refers to a protein or protein moiety that can be bound by or interacted with a compound described herein, such as a compound having a structure from the group of Compound A. In certain embodiments, the target protein is a STIM protein. In certain embodiments, the target protein is an Orai protein.

[0168] As used herein, "STIM protein" includes, but is not limited to, mammalian STIM-1, such as human and rodent (e.g., mouse) STIM-1, Drosophila melanogaster D-STIM, Caenorhabditis elegans C-STIM, Anopheles gambiae STIM, and mammalian STIM-2, such as human and rodent (e.g., mouse) STIM-2 (see U.S. Patent Application Publication No. 2007 / 0031814, paragraphs

[0270] -

[0211] as well as Table 3, which are incorporated by reference herein). As described herein, such proteins have been identified as being involved in, associated with, and / or providing for store-operated calcium entry or regulation thereof, cytoplasmic calcium buffering, and / or regulation of calcium levels within intracellular calcium stores (e.g., the endoplasmic reticulum), or movement of calcium to, within, or out of intracellular calcium stores.

[0169] As used herein, "Orai protein" includes Orai (SEQ ID NO: 1 described in WO 07 / 081804), Orai2 (SEQ ID NO: 2 described in WO 07 / 081804), or Orai3 (SEQ ID NO: 3 described in WO 07 / 081804). The Orai nucleic acid sequence corresponds to GenBank Accession No. NM_032790, the Orai2 nucleic acid sequence corresponds to GenBank Accession No. BC069270, and the Orai3 nucleic acid sequence corresponds to GenBank Accession No. NM_152288. As used herein, Orai refers to any one of the Orai genes, e.g., Orai1, Orai2, Orai3 (see Table I of WO 07 / 081804). As described herein, such proteins have been identified as being involved in, associated with, and / or providing for store-operated calcium entry or regulation thereof, cytoplasmic calcium buffering, and / or regulation of calcium levels in intracellular calcium stores (e.g., the endoplasmic reticulum), or movement of calcium to, within, or out of intracellular calcium stores.

[0170] The term "fragment" or "derivative" when referring to a protein (e.g., STIM, Orai) refers to a protein or polypeptide that retains essentially the same biological function or activity as the native protein in at least one assay. For example, a fragment or derivative of a reference protein maintains at least about 50% of the activity of the native protein, at least 75%, at least about 95% of the activity of the native protein, as determined, for example, by a calcium flux assay.

[0171] As used herein, amelioration of symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to any decrease in severity, delay in onset, slowing of progression, or shortening in duration, whether permanent or temporary, persistent or transient, that may result from or be associated with the administration of the compound or composition.

[0172] The term "modulate," as used herein, means to interact with a target protein directly or indirectly to modify the activity of the target protein, including, by way of example only, inhibition of the target or limiting or reducing the activity of the target.

[0173] As used herein, the term "modulator" refers to a compound that modifies the activity of a target. For example, a modulator can cause an increase or decrease in the magnitude of a particular activity of a target, compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor that reduces the magnitude of one or more activities of a target. In certain embodiments, an inhibitor completely prevents one or more activities of a target.

[0174] As used herein, "modulation" with respect to intracellular calcium refers to any change or adjustment of intracellular calcium, including, but not limited to, changes in calcium concentration in the cytoplasm and / or intracellular calcium storage organelles, such as the endoplasmic reticulum, and changes in the kinetics of calcium influx inside, outside, and within a cell. In embodiments, modulation refers to reduction.

[0175] As used herein, the term "target activity" refers to a biological activity that can be regulated by a modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or disorder.

[0176] The terms "inhibits," "inhibiting," or "inhibitor" with respect to SOC or CRAC channel activity, as used herein, refer to the inhibition of store-operated calcium channel activity or calcium release-activated calcium channel activity.

[0177] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the health of the subject being treated.

[0178] The term "pharmaceutical acceptable," as used herein, refers to a material, such as a carrier, diluent, or formulation, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesired biological effects or interacting adversely with any of the compositions in which the compound is included.

[0179] The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining more than one active ingredient, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that one active ingredient, for example a compound having a structure from the group of compound A and a co-medication, are administered to a patient as separate entities simultaneously, simultaneously or sequentially without any specific time-limited intervening, such that effective levels of the two compounds are provided to the patient's body. The latter also applies to cocktail therapy, for example the administration of three or more active ingredients.

[0180] The term "pharmaceutical composition" refers to a mixture of a compound having a structure from the group of compound A described herein and other chemical components such as carriers, stabilizers, diluents, surfactants, dispersants, suspending agents, thickeners, and / or excipients. Pharmaceutical compositions facilitate the administration of a compound to an organism. Numerous techniques for administering a compound exist in the art, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ocular administration, subcutaneous administration, intramuscular administration, pulmonary administration, and topical administration.

[0181] The term "effective amount" or "therapeutically effective amount" as used herein refers to an amount of an administered drug or compound sufficient to alleviate to some extent one or more of the symptoms of the disease or disorder being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desired alteration of a biological system. For example, an "effective amount" in therapeutic applications is the amount of a composition comprising a compound having a structure from the Compound A group that is required to cause a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case may optionally be determined using techniques such as dose escalation studies.

[0182] The terms "enhance" or "enhancing," as used herein, means to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0183] Terms such as "co-administration," as used herein, are intended to encompass the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0184] The term "carrier," as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.

[0185] The term "diluent" refers to a chemical compound used to dilute a compound of interest prior to delivery. Diluents can also be used to stabilize compounds, as they can provide a more stable environment. Salts dissolved in buffered solutions (which can also control or maintain pH) are utilized as diluents in the art, including but not limited to phosphate buffered saline.

[0186] A "metabolite" of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized" as used herein refers to the totality of processes (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is transformed by an organism. Thus, enzymes may cause specific structural alterations in compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of the compounds to a host and analysis of multiple tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds.

[0187] "Bioavailability" refers to the percentage of the weight of the compound disclosed herein (e.g., a compound from the Compound A group) that is delivered to the systemic circulation of the animal or human being being tested. The total exposure (AUC(0-∞)) of a drug when administered intravenously is usually defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which the compound disclosed herein is absorbed into the systemic circulation when the pharmaceutical composition is taken orally, compared to intravenous injection.

[0188] "Plasma concentration" refers to the concentration of a compound having a structure from the group of Compound A in the plasma component of a subject's blood. It is understood that the plasma concentration of the compounds described herein may vary significantly between subjects due to variability in metabolism and / or possible interactions with other therapeutic agents. According to one embodiment disclosed herein, the plasma concentration of the compounds disclosed herein may vary from subject to subject. Similarly, values ​​such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration-time curve (AUC(0-∞)) may vary from subject to subject. Due to this variability, the amount required to constitute a "therapeutically effective amount" of a compound may vary from subject to subject.

[0189] As used herein, "calcium homeostasis" refers to the maintenance of the overall balance within a cell of intracellular calcium levels and movement, including calcium signaling.

[0190] As used herein, "intracellular calcium" refers to calcium located within a cell without specifying a particular cellular location. In contrast, "cytosol" or "cytoplasm" with respect to calcium refers to calcium located within the cytoplasm.

[0191] As used herein, an effect on intracellular calcium is any change in any aspect of intracellular calcium, including, but not limited to, changes in intracellular calcium levels, and the location and movement of calcium into, out of, or within a cell or intracellular calcium stores or organelles. For example, an effect on intracellular calcium can be a change in the characteristics, such as, for example, the kinetics, sensitivity, velocity, amplitude, and electrophysiological properties, of calcium influx or movement occurring in a cell or a portion thereof. An effect on intracellular calcium can be a change in any intracellular calcium regulatory process, including store-operated calcium influx, cytoplasmic calcium buffering, and calcium levels or calcium movement into, out of, or within an intracellular calcium store. All of these aspects can be evaluated in a variety of ways, including, but not limited to, assessment of calcium or other ion (specifically cation) levels, calcium or other ion (specifically cation) movement, fluctuations in calcium or other ion (specifically cation) levels, kinetics of calcium or other ion (specifically cation) influx, and / or transport of calcium or other ion (specifically cation) across a membrane. The change can be any such change that is statistically significant. Thus, for example, when intracellular calcium in test and control cells is said to be different, such difference may be a statistically significant difference.

[0192] As used herein, "involved in" with respect to the relationship between a protein and an aspect of intracellular calcium or intracellular calcium regulation means that when the expression or activity of the protein in a cell is reduced, altered, or eliminated, there is an associated or associated reduction, alteration, or elimination of one or more aspects of intracellular calcium or intracellular calcium regulation. Such a change or reduction in expression or activity can occur by altering the expression of the gene encoding the protein, or by altering the level of the protein. Thus, a protein involved in an aspect of intracellular calcium, such as store-operated calcium entry, can be a protein that provides or is involved in an aspect of intracellular calcium or intracellular calcium regulation. For example, a protein that provides store-operated calcium entry can be a STIM protein and / or an Orai protein.

[0193] As used herein, a protein that is a component of a calcium channel is a protein that participates in the multiprotein complex that forms the channel.

[0194] As used herein, "basal" or "resting" with respect to cytoplasmic calcium levels refers to the concentration of calcium in the cytoplasm of a cell, such as, for example, an unstimulated cell, that is not subject to conditions that result in calcium movement into or out of a cell. Basal or resting cytoplasmic calcium levels can be the concentration of free calcium (i.e., calcium not bound to cellular calcium-binding substances) in the cytoplasm of a cell, such as, for example, an unstimulated cell, that is not subject to conditions that result in calcium movement into or out of a cell.

[0195] As used herein, "translocation" with respect to ions, including cations, such as calcium, refers to the movement or relocation, e.g., influx, of ions into, out of, or within a cell. Thus, ion movement can be, for example, from the extracellular medium to the cell, from within the cell to the extracellular medium, from within an intracellular organelle or storage site to the cytosol, from the cytosol to an intracellular organelle or storage site, from one intracellular organelle or storage site to another intracellular organelle or storage site, from the extracellular medium to an intracellular organelle or storage site, from an intracellular organelle or storage site to the extracellular medium, and from one location in the cytoplasm to another.

[0196] As used herein, "cation influx" or "calcium influx" refers to the influx of cations, such as calcium, into an intracellular location, such as the cytoplasm of a cell, or into the lumen of an intracellular organelle or storage site. Thus, cation influx can be, for example, the movement of cations from the extracellular medium or an intracellular organelle or storage site to the cytoplasm, or the movement of cations from the cytoplasm or extracellular medium to an intracellular organelle or storage site. The movement of calcium from an intracellular organelle or storage site to the cytoplasm is also referred to as "calcium release" from the organelle or storage site.

[0197] As used herein, "proteins that regulate intracellular calcium" refer to any cellular protein that is involved in the regulation, control, and / or modification of intracellular calcium. For example, such proteins may be involved in the modification or regulation of intracellular calcium in several ways, including, but not limited to, through the maintenance of resting or basal cytoplasmic calcium levels, or through participation in cellular responses to signals transmitted within the cell through mechanisms that involve deviation of intracellular calcium from a resting or basal state. In the context of "proteins that regulate intracellular calcium," a "cellular" protein is a protein associated with a cell, such as, for example, a cytoplasmic protein, a plasma membrane-associated protein, or an intracellular membrane protein. Proteins that regulate intracellular calcium include, but are not limited to, ion transport proteins, calcium binding proteins, and regulatory proteins that control ion transport proteins.

[0198] As used herein, "cellular response" refers to any cellular response resulting from ion movement within or outside of a cell. A cellular response may relate to any cellular activity that is at least partially dependent on ions, such as calcium. Such activities may include, for example, cell activation, gene expression, endocytosis, exocytosis, cell trafficking, and apoptotic cell death.

[0199] As used herein, "immune cells" include cells of the immune system and cells that perform a function or activity in an immune response, such as, but not limited to, T cells, B cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, leukocytes, antigen-presenting cells, and natural killer cells.

[0200] As used herein, "cytokine" refers to a small soluble protein secreted by a cell that can modify the behavior or properties of the secreting cell or another cell. Cytokines bind to cytokine receptors and induce a behavior or property within the cell, such as cell proliferation, cell death, or cell differentiation. Exemplary cytokines include, but are not limited to, interleukins (e.g., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-1α, IL-1β, and IL-1RA), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin M, erythropoietin, leukemia inhibitory factor (LIF), interferons, B7.1 (also known as CD80), B7.2 (also known as B70, CD86), TNF family members (TNF-α, TNF-β, LT-β, ​​CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail), and MIF.

[0201] "Store-operated calcium entry" or "SOCE" refers to a mechanism by which release of calcium ions from intracellular stores is coordinated with ion influx across the plasma membrane.

[0202] A "selective inhibitor of SOC channel activity" means that the inhibitor is selective for the SOC channel and does not substantially affect activity of other types of ion channels.

[0203] By "selective inhibitor of CRAC channel activity" is meant that the inhibitor is selective for the CRAC channel and does not substantially affect the activity of other types of ion channels and / or other SOC channels.

[0204] As used herein, the term "calcium" refers to the element or the divalent cation Ca 2+ may be used to refer to

[0205] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the disclosure. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of the claims and their equivalents are covered thereby. EXAMPLES

[0206] Example 1: Efficacy and recovery of Auxora compared to placebo. Tables 1-4 below provide data for patients treated with placebo or Auxora. Table 1 summarizes efficacy data regarding mortality for patients receiving placebo and patients treated with Auxora through 60 days.

[0207] [Table 1]

[0208] Table 2 summarizes the demographics in the study comparing placebo-treated patients with Auxora-treated patients.

[0209] [Table 2]

[0210] Table 3 summarizes the primary outcome measures for time to recovery for patients treated with placebo compared to Auxora. As shown in the table below, patients treated with Auxora had 3 fewer days of recovery compared to patients treated with placebo.

[0211] [Table 3]

[0212] Table 4 summarizes the safety data comparing placebo to Auxora. Patients who experienced serious adverse events (SAEs) are compared between placebo-treated and Auxora-treated patients in Table 4 below.

[0213] [Table 4]

[0214] Recent results from human clinical trials indicate that intravenous Auxora is safe in critically ill patients and may reduce the severity and duration of respiratory failure compared to (-2-yl)-2-fluoro-6-methylbenzamide-injectable emulsion (IE) control. Both preclinical and clinical data support the development of Auxora for use in patients with ALI / ARDS associated with COVID-19 infection.

[0215] Example 2: Phase 2 clinical trial. A Phase 2 clinical trial was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the pharmaceutical compositions disclosed herein for long-term treatment of subjects at risk of developing ALI and / or ARDS, such as those suffering from COVID-19 or other respiratory viruses / bacteria that result in ALI / ARDS.

[0216] Number of patients and sites: Up to 240 patients with confirmed COVID-19 pneumonia with baseline supplemented PaO2 / FiO2 ≤200 and receiving oxygen therapy via high-flow nasal cannula (HFNC) or noninvasive ventilation (NIV) at up to approximately 40 enrolled sites.

[0217] Dose and route of administration of Auxora and placebo: All patients will receive 2.0 mg / kg (1.25 mL / kg) of Auxora at hour 0 and 1.6 mg / kg (1 mL / kg) at both 24 and 48 hours from the start of the initial Auxora infusion (SFIA) at hour 0. Patients with severe hypoxemic respiratory failure, patients receiving HFNC with a documented worst complement PaO2 / FiO2 <100 between the end of the 24 hour Auxora infusion and the start of the 48 hour Auxora infusion, or patients receiving NIV or invasive mechanical ventilation (IMV) at the start of the 48 hour Auxora infusion will be randomized 1:1 to receive 1.6 mg / kg (1 mL / kg) of Auxora or 1 mL / kg placebo at 72, 96, and 120 hours after the SFIA. All doses of Auxora and placebo will be administered intravenously as a continuous infusion over four hours via a lipid emulsion compatible bag and tubing using a 1.2 micron filter.

[0218] Hypothesis: The pathophysiological course of COVID-19 pneumonia progresses in two distinct phases. Initial viral replication is followed by an excessive and dysregulated host immune response, resulting in alveolitis and hypoxic respiratory failure. Current evidence suggests that alveolitis results from a positive feedback loop between monocyte-derived alveolar macrophages and T cells. Tissue-resident alveolar macrophages (TRAMs) respond to SARSCoV-2 infection in the lungs by producing T cell chemoattractants. Arrival of T cells results in the production of interferon gamma (IFNγ), leading to further alveolar macrophage activation and recruitment of monocyte-derived alveolar macrophages. This feedback loop leads to a rapid increase in proinflammatory cytokines, diffuse alveolar damage, and severe endotheliitis, resulting in acute respiratory distress syndrome (ARDS), as well as multiple organ dysfunction and failure.

[0219] Calcium release-activated calcium (CRAC) channels play an important pathogenic role in several cell types and cellular pathways relevant to COVID-19 pneumonia. Activation of CRAC channels stimulates the production and release of proinflammatory cytokines from immune cells, including those elevated by SARS-CoV-2 infection (e.g., IFN-γ, IL-6, IL-17, and TNFα). Pathophysiological activation of CRAC channels has also been linked to pulmonary endothelial cell dysfunction and plasma extravasation in animal models of acute lung injury. Finally, although the role of CRAC channels in monocyte function is still emerging, it has been shown that the release of reactive oxygen species from monocytes is controlled by Orail CRAC channels.

[0220] Inhibition of CRAC channels may provide a broad class of approaches that are likely to be effective in treating patients with severe COVID-19 pneumonia. Auxora, a calcium release-activated calcium (CRAC) channel inhibitor, potently blocks the production and release of proinflammatory cytokines from immune cells, including those elevated by SARS-CoV-2 infection. Auxora reduced inflammation and plasma extravasation in animal models of acute lung injury, indicating preservation of endothelial integrity. In addition, Ca2+ entering through CRAC channels in T cells primarily activates the calcineurin / NFAT signaling pathway, so Auxora may function synergistically with anti-inflammatory drugs such as dexamethasone that act through the NF-κB signaling pathway. Auxora is administered intravenously and distributed to the lungs within 2 to 4 hours of the start of infusion, exhibiting a rapid onset of activity with IL-2 production decreasing by more than 50% at the end of infusion, and does not appear to have a long-term immunomodulatory effect, with IL-2 production recovering 24 hours after the end of infusion.

[0221] Auxora is being tested in a randomized, double-blind, placebo-controlled trial in patients with severe COVID-19 pneumonia being treated with corticosteroids (CARDEA; NCT04345614). In patients with baseline imputed PaO2 / FiO2 ≤ 200 (n = 261), median time to recovery was 7 and 10 days in patients receiving Auxora and placebo, respectively (P = 0.0979). All-cause mortality at 60 days in these patients was 13.8% with Auxora versus 20.6% with placebo (p = 0.1449). All-cause mortality at 30 days was 7.7% and 17.6%, respectively (p = 0.0165). In the subgroup of patients (n=162) receiving HFNC oxygen therapy at baseline, all-cause mortality at day 60 was 16.0% with Auxora versus 25.6% with placebo (p=0.1436). In the subgroup of patients (n=117) with baseline imputed PaO2 / FiO2 <100, a similar decline was observed at day 60: 20.3% with Auxora versus 29.3% with placebo. Fewer patients treated with Auxora (24.1%) had serious adverse events (SAEs) than placebo (35.0%), and fewer patients discontinued study drug due to adverse events (AEs) or toxicity with Auxora (n=3) versus placebo (5).

[0222] In CARDEA, 81 patients receiving HFNC at baseline were treated with Auxora. Eight of the 81 patients were undergoing IMV at 48 hours at the start of the infusion. Four of the eight patients subsequently died. Thirty-nine patients had a worst supplemental PaO2 / FiO2 >100 between the end of the Auxora infusion at 24 hours and the start of the Auxora infusion at 48 hours. Only two of the 39 patients continued to require IMV or died. Thirty-four patients had a worst supplemental PaO2 / FiO2 ≤100 between the end of the Auxora infusion at 24 hours and the start of the Auxora infusion at 48 hours. Thirteen of the 34 patients continued to require IMV and / or died.

[0223] Data from CARDEA suggest potential benefit and safety of Auxora in patients with severe and critical COVID-19 pneumonia. They also identify subgroups of patients at high risk of disease progression and death who may benefit from additional days of Auxora. Therefore, this study aims to further explore the safety and clinical efficacy of Auxora in patients with severe COVID-19 pneumonia, as well as the clinical efficacy of Auxora at the 6:3 dose in patients at high risk of disease progression and death, as standard of care continues to evolve to include other immunomodulatory agents beyond corticosteroids.

[0224] Primary Objectives: To evaluate the safety and tolerability of Auxora when administered to patients receiving corticosteroids and tocilizumab as standard of care. To evaluate the clinical efficacy of Auxora at 6 doses versus 3 doses in randomized patients with severe hypoxemic respiratory failure, patients receiving HFNC with a documented worst complemented PaO2 / FiO2 <100 between the end of Auxora infusion at 24 hours and the start of Auxora infusion at 48 hours, or patients receiving NIV or IMV at the start of Auxora infusion at 48 hours.

[0225] Secondary Objectives: To assess the safety and tolerability of Auxora in patients with severe COVID-19 pneumonia receiving oxygen therapy with HFNC or NIV at baseline. To assess the pharmacokinetic properties of Auxora in patients with severe COVID-19 pneumonia.

[0226] Inclusion Criteria: Patients must meet all of the following to be enrolled in this study: 1. Laboratory confirmation of SARS-CoV-2 infection, as determined by polymerase chain reaction (PCR) or other commercial or public health assay on any specimen, documented by any of the following: - PCR positive sample collected within 72 hours of consent - A positive PCR result on a sample collected more than 72 hours prior to consent and a repeat sample cannot be obtained (e.g., due to lack of testing supplies, or limited testing capacity, or results taking more than 24 hours to obtain), or there is progressive illness indicative of progression of SARS-CoV-2 infection. 2. At least one of the following symptoms is present: Fever, cough, sore throat, fatigue, headache, muscle pain, difficulty breathing at rest or on exertion, confusion, or shortness of breath 3. PaO2 / FiO2 recorded 24 hours prior to consent was 200 or less. PaO2 / FiO2 can be supplemented by pulse oximetry (Figure 7). 4. Oxygen therapy is being administered via HFNC or NIV. 5. There is respiratory infiltrate or abnormality consistent with pneumonia documented by either CXR or CT scan of the lungs. 6.Patients aged 18 years or older. 7. Female patients of childbearing potential must not attempt to become pregnant for 180 days and, if sexually active with a male partner, are willing to use acceptable contraception for 180 days after the last dose of study drug. 8. Male patients who are sexually active with a female partner of childbearing potential are willing to use acceptable contraception for 180 days after the last dose of study drug. Male patients must not donate sperm for 180 days. 9. Patient who has provided informed consent to participate and is willing and able, or has a legally authorized representative (LAR) who is willing and able, to cooperate in all aspects of the protocol.

[0227] Exclusion Criteria: Patients with any of the following conditions or characteristics at the time of screening must be excluded from enrollment: 1. You do not want to be intubated. 2. PaO2 / FiO2 at the time of consent was recorded as 75 or less. PaO2 / FiO2 can be supplemented by pulse oximetry (Figure 7). 3. Receiving IMV via endotracheal intubation or tracheotomy. 4. Receiving ECMO. 5. Shock occurs due to the use of vasoconstrictors. 6. The following is known to have occurred: a. Organ or blood transplants, B. HIV, c. Active hepatitis B or C infection 7. Currently undergoing treatment with: a.Chemotherapy, b. Immunosuppressant medications or immunotherapies at the time of consent (see below for a list of prohibited immunosuppressant medications and immunotherapies); C. Artificial dialysis or peritoneal dialysis 8. Pregnant or breastfeeding. 9.Currently participating in a study involving another investigational drug or therapeutic medical device at the time of consent. 10. Known allergy to eggs or any of the excipients in the investigational drug.

[0228] Study Design: All patients who meet all inclusion criteria and none of the exclusion criteria will receive three doses of Auxora: 2.0 mg / kg (1.25 mL / kg) at 0 hours, followed by 1.6 mg / kg (1 mL / kg) at 24 hours, and 1.6 mg / kg (1 mL / kg) at 48 hours via SFIA.

[0229] Patients with severe hypoxemic respiratory failure, patients receiving HFNC with a worst recorded complementary PaO2 / FiO2 below 100 between the end of Auxora infusion at 24 hours and the start of Auxora infusion at 48 hours, or patients receiving NIV or IMV at the start of Auxora infusion at 48 hours will be randomized 1:1 to receive 1.6 mg / kg (1 mL / kg) Auxora or 1 mL / kg placebo at 72 hours, 96 hours, and 120 hours after the SFIA. Patients receiving IMV will be stratified between the Auxora and placebo groups.

[0230] Patients without severe hypoxemic respiratory failure, those with a recorded worst complementary PaO2 / FiO2 >100 between the end of Auxora infusion at 24 hours and the start of Auxora infusion at 48 hours, and those not receiving NIV or IMV will not be randomized for further infusions but will continue in the study and complete all evaluations by day 60.

[0231] Dosing of Auxora and placebo will be based on actual body weight obtained at admission or study screening. As described in the pharmacy manual, there is an upper limit on the absolute dose (volume) of Auxora and volume of placebo administered to patients weighing more than 125 kg.

[0232] The study investigator or an appropriately trained delegate will perform assessments in all patients at screening, immediately prior to the SFIA, and immediately prior to each subsequent infusion at 24 and 48 hours after the SFIA.

[0233] For patients randomized to receive further doses of investigational drug, assessments will be performed prior to each infusion at 72, 96, and 120 hours after SFIA. Patients will then be assessed every 24 hours (± 4 hours) starting 144 hours after SFIA until 336 hours after SFIA, and then every 48 hours thereafter until discharge or day 60. For safety and mortality assessments, all patients discharged before day 25 will be followed up on day 30 (± 5 days). All patients discharged on day 25 or later but before day 30 will use the discharge assessment as the day 30 assessment. For safety and mortality assessments, all patients will be followed up on day 60 (± 5 days). All patients discharged on day 55 or later but before day 60 will use the discharge assessment as the day 60 assessment.

[0234] For patients not randomized to receive additional study medication, patients will be assessed every 24 hours (± 4 hours) starting 72 hours after SFIA until 336 hours after SFIA, and then every 48 hours until discharge or day 60. For safety and mortality assessments, all patients discharged before day 25 will be followed up to day 30 (± 5 days). All patients discharged on day 25 or later but before day 30 will use the discharge assessment as the day 30 assessment. For safety and mortality assessments, all patients will be followed up to day 60 (± 5 days). All patients discharged on day 55 or later but before day 60 will use the discharge assessment as the day 60 assessment.

[0235] An Independent Data Monitoring Committee (IDMC) will evaluate safety data from the study after the initial enrollment of approximately 50 patients, and then again after enrollment of approximately 100 and 200 patients. Information regarding IDMC reviews and the timing of IDMC meetings is further detailed in the study's IDMC Charter.

[0236] All patients enrolled in this study should receive treatment consistent with the national standard of care. Patients with worsening respiratory failure should receive a conservative intravenous fluid strategy, such as FACTT LITE. All patients should receive pharmacological prophylaxis to prevent progression of venous thromboembolic disease. The type and dose of prophylaxis should be determined by the national standard of care.

[0237] Patients enrolled in the study must receive dexamethasone or an equivalent dose of another corticosteroid as standard of care. If a patient is not receiving dexamethasone at the time of enrollment in CARDEA-Plus, dexamethasone or an equivalent dose of another steroid must be initiated. If a patient is already receiving dexamethasone at the time of enrollment, dexamethasone must be continued on its established dosing schedule. The National Institutes of Health COVID-19 Treatment Guidelines Panel recommends the use of dexamethasone (6 mg / day, orally or intravenously, for up to 10 days) for COVID-19 patients who require supplemental oxygen. Notably, the equivalent doses of 6 mg dexamethasone per day are 40 mg prednisone per day, 32 mg methylprednisolone per day, and 160 mg hydrocortisone per day.

[0238] If the patient is not receiving remdesivir at the time of enrollment in CARDEA-Plus, initiation of remdesivir during hospitalization may be considered. If the patient is already receiving remdesivir at the time of enrollment, remdesivir should be continued on its established dosing schedule. The suggested remdesivir dose for adults weighing ≥40 kg and not requiring invasive mechanical ventilation and / or ECMO is a single dose of 200 mg infused intravenously over 30-120 minutes on day 1, followed by once-daily maintenance doses of 100 mg infused intravenously over 30-120 minutes for 4 days (days 2-5). Treatment may be extended for up to 5 additional days if the patient does not demonstrate clinical improvement.

[0239] (i.e., a maximum of 10 days total). Auxora and Remdesivir should not be infused at the same time and should be given sequentially, but may be given in any order.

[0240] For patients with evidence of systemic inflammation and the need for oxygen surge within 3 days of admission, tocilizumab at 8 mg / kg actual body weight (maximum 800 mg) administered as a single IV dose may be considered. Approximately one-third of patients in the REMAP-CAP and RECOVERY trials received a second dose of tocilizumab at the discretion of the treating physician, but no data are available on outcomes based on one or two doses. Thus, there is insufficient evidence, if any, to determine which patients would benefit from an additional dose of tocilizumab.

[0241] Other immunosuppressive medications or immunotherapies are prohibited for patients enrolled in this study (see list of prohibited medications below). The use of dextromethorphan is to be withheld for patients enrolled in this study.

[0242] Prohibited list of immunosuppressive drugs and immunotherapies: chemotherapy, cyclosporine, tacrolimus, sirolimus, everolimus, azathioprine, cyclophosphamide, methotrexate, mycophenolate, leflunomide, abatacept, adalimumab, alemtuzumab, anakinra, basilizimab, belimumab, bevacizumab, brodalumab, canakinumab, certolizumab , cetuximab, clazakizumab, daclizumab, eculizumab, etanercept, golimumab, infliximab, interferon, ixekizumab, muromonab, natalizumab, omalizumab, rituximab, sarilumab, secukinumab, trastuzumab, ustekinumab, vedolizumab, baricitinib, tofacitinib, or other Janus kinase inhibitors. Further use of dextromethorphan is not recommended.

[0243] Efficacy endpoints: Efficacy endpoints included the following: Primary efficacy endpoint Proportion of randomized patients receiving 6 vs. 3 doses of Auxora requiring IMV after 72 hours or death up to 60 days after SFIA Secondary efficacy endpoints All-cause mortality up to 60 days in patients randomized to receive 6 doses vs. 3 doses of Auxora All-cause mortality up to 30 days in patients randomized to receive 6 doses vs. 3 doses of Auxora Proportion of randomized patients receiving 6 vs. 3 doses of Auxora requiring IMV from 72 hours after SFIA through Day 60 Length of stay in hospital Number of days in ICU Exploratory endpoints -Decrease in angiopoietin levels after treatment with Auxora Increase in angiopoietin levels after treatment with Auxora

[0244] Safety endpoints: Safety endpoints included: Safety endpoints included: Incidence of TEAEs and SAEs ·Relationship with TEAE and SAE strength Clinically significant changes in vital signs and safety test results

[0245] Sample size calculations: For a 1:1 treatment allocation ratio (Auxora:placebo) in the random allocation phase, a two-arm chi-square test with a 5% two-sided significance level has 70% power to detect a difference between a placebo rate of 42% and an Auxora rate of 20% (odds ratio of 0.35) in need of IMV after 72 hours or death by day 60 from SFIA, with a sample size of 54 in each arm. Sample sizes for the random allocation phase were estimated using nQuery v8.4 from statistical solutions ltd.

[0246] Based on CARDEA, the percentage of enrolled patients receiving HFNC with a documented worst complemented PaO2 / FiO2 of 100 or less between the end of Auxora infusion at 24 hours and the start of Auxora infusion at 48 hours, or the percentage of enrolled patients receiving NIV or invasive mechanical ventilation (IMV) at the start of Auxora infusion at 48 hours, is estimated to be 50%. A total of 216 subjects are expected to need to be enrolled to meet the need for 54 subjects randomized to the Auxora and Placebo groups. Assuming an initial decline rate of 10%, approximately 240 subjects will be enrolled in the study.

[0247] CARDEA CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating Auxora, a CRAC channel inhibitor, plus corticosteroids and standard of care in adults with severe COVID-19 pneumonia. The primary endpoint was time to recovery by day 60, with recovery defined as being in one of three categories: hospitalization without need for supplemental oxygen or continuing medical care, discharge requiring supplemental oxygen, and discharge not requiring supplemental oxygen. Key secondary endpoints were all-cause mortality at day 60 and day 30. The trial was stopped early due to declining rates of COVID-19 hospitalization in the United States and the encroachment of banned drugs as standard of care.

[0248] Overall, 143 patients were randomized to Auxora and 141 to placebo. 100% of patients in both the Auxora and placebo groups received corticosteroids. In patients who received at least one dose of study drug (n=281), median recovery times were 7 and 8 days in patients receiving Auxora and placebo, respectively (P=0.0420). In patients with baseline imputed PaO2 / FiO2 ≤200 (n=261), recovery times were 7 days in patients receiving Auxora (n=130) and 10 days in patients receiving placebo (n=131) (P=0.0979). All-cause mortality at 60 days in patients with baseline imputed PaO2 / FiO2 ≤200 was 13.8% in patients receiving Auxora and 20.6% in patients receiving placebo (P=0.1449). All-cause mortality at 30 days was 7.7% and 17.6%, respectively (p=0.0165).

[0249] A similar trend in faster recovery and lower mortality was observed in the prespecified subgroup of patients receiving HFNC at baseline (n=163). Eighty-one patients were randomized to Auxora and 82 patients were randomized to placebo. The median time to recovery for patients receiving Auxora was 9 days compared with 17 days for patients receiving placebo (P=0.1079). At day 60, all-cause mortality was 16% for patients receiving HFNC at baseline receiving Auxora compared with 25.6% for patients receiving placebo (P=0.1436).

[0250] In CARDEA, Auxora was found to be safe and well tolerated, with few patients experiencing serious adverse events and adverse events requiring discontinuation of treatment. Overall, 34 patients (24.1%) receiving Auxora and 49 patients (35.0%) receiving placebo experienced SAEs; the most common were respiratory failure, ARDS, and pneumonia. Discontinuation due to TEAEs occurred in three patients receiving Auxora and five patients receiving placebo (Table 5).

[0251] [Table 5]

[0252] The most common TEAEs were respiratory failure, elevated triglycerides, hyperglycemia, and acute kidney injury. All cases of elevated triglycerides in both the Auxora and placebo groups were classified as mild. No cases of hyperglycemia were reported as severe (Table 6).

[0253] [Table 6]

[0254] Mechanistically, CRAC channel inhibitors such as Auxora may have therapeutic benefits in both hastening recovery and reducing mortality in severe COVID-19 pneumonia, so continued clinical development is warranted. CARDEA results demonstrated that Auxora is safe and well tolerated for its strong signal in both recovery time and all-cause mortality. This benefit may be due in part to synergy with corticosteroids administered as standard of care. In T cells, CRAC channels are known to be proximal components of the calcium-dependent pathway leading to activation of calcineurin, as well as NFAT, a transcription factor that controls the production of IL-2 and other cytokines. Thus, CRAC channel inhibitors act in part by reducing the activation of NFAT in stimulated T cells. On the other hand, corticosteroids such as dexamethasone are thought to mediate their immunomodulatory effects through a different transcription factor, NF-κB (Grundy et al., Clin Sci, 2014), and therefore their effects on inflammatory cells may be complementary to those of CRAC channel inhibitors.

[0255] Tocilizumab and baricitinib are currently recommended for patients recently hospitalized with COVID-19 pneumonia who have evidence of oxygen surge requirements and systemic inflammation. CRAC channel inhibition may also synergize with IL-6 receptor blockade in improving outcomes in severely ill patients with COVID-19 pneumonia by reducing the production of multiple proinflammatory cytokines, such as IL-17 and IFNγ, all of which are involved in the pathogenesis of SARS-CoV-2-induced alveolitis (Parrot et al., Immunol, 2020; Grant et al., Nature, 2021). Possible synergy with baricitinib is currently unknown.

[0256] The immunomodulatory effects of Auxora are not expected to be additive with IL-6 blockers such as tocilizumab. The potential for such Auxora to increase the immunomodulatory effects of baricitinib is uncertain at this time, which is why baricitinib is excluded from the study. Based on human PK / PD data, the recommended dose of tocilizumab at 8mg / kg is expected to inhibit IL-6 binding to its receptor by more than 95%, essentially abolishing IL-6 signaling, as long as serum tocilizumab levels remain above 1μg / mL, despite tocilizumab inducing elevated serum IL-6 levels. It stands to reason, then, that any inhibition of IL-6 production and release provided by Auxora (CM4620) will not enhance the inhibition of IL-6 signaling already provided by tocilizumab or any other IL-6 blocker at comparable doses. Thus, the immunomodulatory effects of Auxora, mediated by reduced IL-6 signaling, are not expected to be additive or synergistic with IL-6 blockers such as tocilizumab.

[0257] Pharmacodynamic studies in patients with acute pancreatitis showed that the effects of Auxora on immune cells were moderate in nature and rapidly reversed with the cessation of treatment. There was no increase in serious adverse events related to secondary infections with Auxora treatment observed in CARDEA. However, the present study is justified to document the safety of Auxora when combined with corticosteroids and tocilizumab. This risk-benefit ratio favors the testing of this combination in patients at highest risk of mortality, those with severe COVID-19 pneumonia requiring noninvasive ventilation or oxygen therapy with HFNC.

[0258] In CARDEA, 81 patients undergoing HFNC at baseline were treated with Auxora. Eight of the 81 patients received IMV at 48 hours at the start of the infusion. Four of the eight patients subsequently died. Thirty-nine patients had a worst supplemental PaO2 / FiO2 >100 between the end of the Auxora infusion at 24 hours and the start of the Auxora infusion at 48 hours. Only two of the 39 patients continued to require IMV or died. Thirty-four patients had a worst supplemental PaO2 / FiO2 ≤100 between the end of the Auxora infusion at 24 hours and the start of the Auxora infusion at 48 hours. Thirteen of the 34 patients continued to require IMV and / or died. High-risk patients receiving HFNC with a PaO2 / FiO2 ≤100 prior to the third infusion of Auxora or receiving NIV or IMV prior to the third infusion of Auxora may potentially benefit from an additional day of Auxora.

[0259] PK modeling suggests that 6 days of Auxora dosing would allow continued treatment for these high-risk patients with an acceptable margin of safety. Results from PK sample analysis from CARDEA were integrated into a population PK model generated from the SAD, MAD, acute pancreatitis studies, and the first open-label study in COVID-19. Modeling suggests that with an initial dose of 2 mg / kg and subsequent doses of 1.6 mg / kg / day for 6 days of dosing, the mean AUC24h on day 6 still provides a greater than 3-fold margin of safety compared to the NOAEL level determined by preclinical monkey toxicology studies, and the maximum AUC24h level is still below the NOAEL level.

[0260] Therefore, the two primary objectives of this study are to evaluate the safety and tolerability of Auxora when administered to patients receiving corticosteroids and tocilizumab as standard of care, and to evaluate the clinical efficacy of 6 doses versus 3 doses of Auxora in randomized patients with severe hypoxemic respiratory failure, patients receiving HFNC who recorded a worst-complemented PaO2 / FiO2 ≤100 between the end of Auxora infusion at 24 hours and the start of Auxora infusion at 48 hours, or patients receiving NIV or IMV at the start of Auxora infusion at 48 hours.

[0261] Patient treatment All patients enrolled in this study should receive treatment consistent with the national standard of care. Patients with worsening respiratory failure should receive a conservative intravenous fluid strategy, such as FACTT LITE. All patients should receive pharmacological prophylaxis to prevent progression of venous thromboembolic disease. The type and dose of prophylaxis should be determined by the national standard of care.

[0262] Patients enrolled in the study must receive dexamethasone or an equivalent dose of another corticosteroid as standard of care. If a patient is not receiving dexamethasone at the time of enrollment in CARDEA-Plus, dexamethasone or an equivalent dose of another steroid must be initiated. If a patient is already receiving dexamethasone at the time of enrollment, dexamethasone must be continued on its established dosing schedule. The National Institutes of Health COVID-19 Treatment Guidelines Panel recommends the use of dexamethasone (6 mg / day, orally or intravenously, for up to 10 days) for COVID-19 patients who require supplemental oxygen. Notably, the equivalent doses of 6 mg dexamethasone per day are 40 mg prednisone per day, 32 mg methylprednisolone per day, and 160 mg hydrocortisone per day.

[0263] If the patient is not receiving remdesivir at the time of enrollment in CARDEA-Plus, initiation of remdesivir during hospitalization may be considered. If the patient is already receiving remdesivir at the time of enrollment, remdesivir should be continued on its established dosing schedule. The suggested remdesivir dose for adults weighing ≥40 kg and not requiring invasive mechanical ventilation and / or ECMO is a single dose of 200 mg infused intravenously over 30-120 minutes on day 1, followed by once-daily maintenance doses of 100 mg infused intravenously over 30-120 minutes for 4 days (days 2-5). If the patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e., up to 10 days in total). Auxora and remdesivir should not be infused simultaneously and should be administered sequentially, but may be administered in any order.

[0264] For patients with evidence of systemic inflammation and the need for oxygen surge within 3 days of admission, tocilizumab at 8 mg / kg actual body weight (maximum 800 mg) administered as a single IV dose may be considered. Approximately one-third of patients in the REMAP-CAP and RECOVERY trials received a second dose of tocilizumab at the discretion of the treating physician, but no data are available on outcomes based on one or two doses. Thus, there is insufficient evidence, if any, to determine which patients would benefit from an additional dose of tocilizumab.

[0265] Other immunosuppressive medications or immunotherapies are prohibited for patients enrolled in this study and are listed below: The use of dextromethorphan is to be withheld for patients enrolled in this study.

[0266] Prohibited Medication: Any medication may be given at the discretion of the PI, except for those listed below. Medications that should not be administered to patients enrolled in the study during this study include the following: Chemotherapy drugs, Cyclosporine, tacrolimus Sirolimus, everolimus Azathioprine Cyclophosphamide Methotrexate Mycophenolate Leflunomide Biologics / Monoclonal Antibodies: Abatacept, Adalimumab, Alemtuzumab, Anakinra, Basilizumab, Belimumab, Bevacizumab, Brodalumab, Canakinumab, Certolizumab, Cetuximab, Clazakizumab, Daclizumab, Eculizumab, Etanercept, Golimumab, Infliximab, Interferon, Ixekizumab, Muromonab, Natalizumab, Omalizumab, Rituximab, Sarilumab, Secukinumab, Trastuzumab, Ustekinumab, Vedolizumab Baricitinib, tofacitinib, or other Janus kinase inhibitors

[0267] Please note that further use of dextromethorphan is not recommended.

[0268] Discharge Criteria: All patients must remain hospitalized until all 3 doses of Auxora have been administered. All randomized patients must remain hospitalized until an additional 3 doses of study drug have been administered.

[0269] If the patient is ready to be discharged before all doses of Auxora or study drug have been administered, the PI or treating physician must contact the medical monitor prior to discharging the patient.

[0270] Compliance: Only the PI, or his / her appropriately trained study collaborators, will administer the investigational product to patients enrolled in the study according to the protocol. The investigational product may not be used for any reason other than as described in the protocol.

[0271] Enrolment and Randomisation Procedures: All enrolled patients will receive three doses of Auxora. Patients undergoing HFNC with a documented worst imputed PaO2 / FiO2 ≤100 between the end of Auxora infusion at 24 hours and the start of Auxora infusion at 48 hours, or patients undergoing NIV or IMV at the start of Auxora infusion at 48 hours, will be randomised 1:1 to receive three additional doses of study medication, either Auxora or volume-matched placebo. Patients undergoing IMV will be stratified between Auxora and placebo groups. Enrolment and randomisation will be performed via a web-based system.

[0272] Discontinuation and Withdrawal: The term discontinuation refers to the patient or PI discontinuing Auxora before all three doses of Auxora have been administered in a randomized patient, even though the patient remains hospitalized. Patients who have not received three doses of Auxora because the treating physician discharged the patient due to rapid improvement are not considered to have discontinued study drug.

[0273] Patients have the right to discontinue administration of Auxora or investigational drug to randomized patients at any time for any reason without interference with medical care and without impacting the medical care of the patient. PIs may discontinue administration of Auxora or investigational drug due to adverse events or changes in medical condition that raise safety concerns for patients receiving additional doses of Auxora or investigational drug. When possible, PIs must communicate with the medical monitor to review the reason for discontinuation of Auxora or investigational drug in patients. PIs must also document the reason for discontinuation in the eCRF and appropriate source documentation at the study site. Care must be taken to ensure that all study visits and assessments are completed on alternate days by the end of the study, even if the patient discontinues administration of Auxora or investigational drug.

[0274] Withdrawal refers only to a patient's complete withdrawal from the study by withdrawal of consent. Patients must request discontinuation of Auxora or investigational drug in lieu of consent withdrawal to ensure they are followed for safety assessments. The PI must inform the medical monitor of the consent withdrawal and document the consent withdrawal in the eCRF and appropriate source documentation at the study site. For all patients who withdraw consent, the investigator must endeavor (within the limits of privacy laws or other regulations) to report the patient's vital status (e.g., dead or alive) at days 30 and 60. Review of publicly available records, such as death registries and / or information available on the internet, may be an appropriate publicly available source.

[0275] Drug Materials and Administration Auxora is administered as an IV infusion and is supplied as a translucent, white to yellow, sterile, nonpyrogenic emulsion containing 1.6 mg / mL of the active pharmaceutical ingredient CM4620. Auxora is supplied in 100 mL disposable glass vials filled with 80 mL. Auxora contains egg phospholipids, medium chain triglycerides, glycerin, edetate disodium salt dehydrate (EDTA), sodium hydroxide (necessary to adjust pH), and sterile water for injection (Table 7).

[0276] [Table 7]

[0277] The matching dose placebo will be administered as an IV infusion and will be supplied in a translucent, white to yellow, sterile, non-pyrogenic emulsion carrier that contains no active pharmaceutical ingredients. Placebo will be supplied in 80 mL filled 100 mL single-use vials. Placebo will contain the same ingredients as Auxora, except that it does not contain CM4620.

[0278] Auxora and placebo must be maintained in a secure location at refrigerated temperatures between 2-8°C (36-46°F). Precautions must be taken to keep Auxora and placebo from freezing. Temperature logs must be maintained and available during monitoring studies. CalciMedica or its designee must be notified as soon as possible if temperatures are observed to be outside the range of 2°C-8°C for more than 24 hours or if temperatures exceed 20°C (68°F) or are below 0°C (32°F). Stability of Auxora and placebo has been demonstrated for up to 24 months and is being evaluated over longer periods in ongoing studies. Investigator management procedures also include details regarding storage of Auxora and placebo, as well as procedures for controlling and reporting temperature fluctuations.

[0279] The study pharmacist and / or designee will be responsible for the preparation and dispensing of Auxora and placebo. Prior to administration, both Auxora and placebo must be transferred using sterile technique into sterile containers. Specific details regarding how to prepare Auxora and placebo, as well as the specific ingredients used to administer both Auxora and placebo, will be provided in the Investigator Administration Procedures. The Investigator Administration Procedures will also be accompanied by tables detailing the selected dose levels and administration volumes of Auxora and placebo.

[0280] Both Auxora and placebo will be administered intravenously over 4 hours at a constant infusion rate. All patients will receive three doses of Auxora every 24 hours (± 1 hour) on three consecutive days. Randomized patients will receive three additional doses of Auxora or placebo. The dose and volume of Auxora administered, as well as the volume of placebo, will be calculated using the patient's weight obtained on admission or during screening. Peripheral or central venous lines may be used for infusion. Peripheral IVs must be 20 gauge or larger in size. Peripheral IV or central line ports should only be used if Auxora or placebo is to be administered in addition to 0.9% saline. Auxora and placebo are compatible with 0.9% saline. IV tubing used to administer Auxora and placebo must contain a 1.2 micron filter. The investigator administration protocol will include recommended procedures for priming IV tubing and flushing the tubing, which may be adapted to national nursing standards. 0.9% saline may be used to flush the line to ensure the planned volume of infusion (VTBI) is administered completely. If administration of Auxora or placebo is stopped for technical reasons such as IV site failure or IV pump malfunction, it should be resumed when the technical reason is resolved and should continue at the same rate until the infusion is completed. The total time from the start of Auxora or placebo infusion to the end of the infusion should be recorded.

[0281] The study may modify the Auxora dose or placebo volume, infusion date, timing of infusion, and infusion rate at any time based on review of safety and tolerability data by the IDMC. If administration of Auxora or placebo is discontinued due to a serious adverse event considered to be probably or definitely related to Auxora or placebo, the Medical Monitor must be contacted immediately.

[0282] Administration of the infusion should be set to be completed over 4 hours, although minor variability is expected based on the equipment used and the calibration of the equipment. The recommended infusion time frame is 4 hours (± 30 minutes). Infusions outside of this time frame will be evaluated to ensure the full dose (>90%) has been administered. If the full dose has not been administered, a protocol deviation will be recorded.

Claims

1. 1. An intracellular calcium signaling inhibitor for use in a method for treating acute lung injury (ALI), acute respiratory distress syndrome (ARDS), COVID-19 pneumonia, bacterial pneumonia, viral pneumonia, acute pancreatitis, or a combination thereof in a subject, said method comprising administering to said subject a therapeutically effective amount of said intracellular calcium signaling inhibitor, wherein said subject has a PaO of about 200 or less. ２ / FiO ２ (P / F) ratio, and said subject has been administered said intracellular calcium signaling inhibitor at least twice.

2. The intracellular calcium signaling inhibitor of claim 1, wherein the subject has a P / F ratio of about 125 or less.

3. The intracellular calcium signaling inhibitor of claim 2, wherein the subject has a P / F ratio of about 100 or less.

4. The intracellular calcium signaling inhibitor of claim 2, wherein the subject has a P / F ratio of about 75 to about 150.

5. An intracellular calcium signaling inhibitor as described in claim 2, wherein the subject shows an increase in the P / F ratio after administration of the intracellular calcium signaling inhibitor.

6. An intracellular calcium signaling inhibitor as described in claim 1, wherein the subject's recovery rate is greater than about 35%, greater than about 50%, greater than about 75%, or greater than about 90%.

7. An intracellular calcium signaling inhibitor as described in claim 1, wherein the recovery rate of the subject is about 50% to about 100%.

8. An intracellular calcium signaling inhibitor as described in claim 1, wherein the subject is further administered oxygen therapy.

9. The intracellular calcium signaling inhibitor described in claim 8, wherein the oxygen therapy is administered by high-flow nasal cannula (HFNC) or non-invasive ventilation (NIV).

10. The intracellular calcium signaling inhibitor of claim 1, wherein the subject has a P / F ratio of about 100 or less after receiving two doses of the intracellular calcium signaling inhibitor, and receives a total of four, five, or six doses in addition to a third dose.

11. The intracellular calcium signaling inhibitor described in claim 1, wherein the intracellular calcium signaling inhibitor is administered at least three times.

12. The intracellular calcium signaling inhibitor described in claim 11, wherein the second administration of the intracellular calcium signaling inhibitor is administered approximately 24 hours after the first administration.

13. The intracellular calcium signaling inhibitor described in claim 11, wherein the third administration of the intracellular calcium signaling inhibitor is administered approximately 48 hours after the first administration.

14. An intracellular calcium signaling inhibitor as described in claim 11, wherein the concentration of the first administration is higher than the concentrations of the second and third administrations.

15. The intracellular calcium signaling inhibitor described in claim 11, wherein the intracellular calcium signaling inhibitor is administered at a concentration of about 0.1 mg / kg to about 5 mg / kg.

16. An intracellular calcium signaling inhibitor as described in claim 11, wherein the first dose is administered at a concentration of approximately 2.0 mg / kg, and the second and third doses are administered at concentrations of approximately 1.6 mg / kg.

17. An intracellular calcium signaling inhibitor as described in claim 15, wherein the concentration of the intracellular calcium signaling inhibitor increases or decreases when the P / F ratio of the subject is similar to the P / F ratio before administration.

18. An intracellular calcium signaling inhibitor as described in claim 1, wherein the ALI or ARDS includes pneumonia.

19. The intracellular calcium signaling inhibitor described in claim 18, wherein the pneumonia includes severe pneumonia, serious pneumonia, or viral pneumonia.

20. The intracellular calcium signaling inhibitor of claim 18, wherein the pneumonia includes severe or critical COVID-19 pneumonia.

21. The intracellular calcium signaling inhibitor is selected from the group consisting of N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin- 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazole-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N- (4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazol-4-yl)methyl)aniline, N-(5-(7-chloro-2,3- dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazol-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)-2,3,6-trifluorobenzamide, N-( 5-(6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)-2,6-difluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2- (trifluoromethyl)oxazol-4-yl)phenyl)benzamide, 2,6-difluoro-N-(5-(2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)benzamide, N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(4-(2-((6-chloropyridin-3-yl)oxy)-4-methylthiazol-5-yl)phenyl)-2-fluorobenzamide, N-( The intracellular calcium signaling inhibitor according to claim 1, which is 5-(2,5-dimethylbenzo[d]oxazol-6-yl)thiazol-2-yl)-2,3,6-trifluorobenzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

22. The intracellular calcium signaling inhibitor is selected from the group consisting of N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazol-5-yl)phenyl)-2-fluorobenzamide, and N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazol-5-yl)phenyl). N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 3-fluoro 4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazol-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl- 1-(thiazol-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)-2,6-difluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, 2,6-difluoro-N-(5-(2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)benzamide, N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(4-(2-((6-chloropyridine-3- 22. The intracellular calcium signaling inhibitor according to claim 21, which is N-(5-(2,5-dimethylbenzo[d]oxazol-6-yl)thiazol-2-yl)-2,3,6-trifluorobenzamide, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

23. The intracellular calcium signaling inhibitor, comprising 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-thiazol- 22. The intracellular calcium signaling inhibitor of claim 21, which is N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

24. The intracellular calcium signaling inhibitor of claim 21, wherein the intracellular calcium signaling inhibitor is N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

25. An intracellular calcium signaling inhibitor for use in a method for treating acute lung injury (ALI), acute respiratory distress syndrome (ARDS), COVID-19 pneumonia, bacterial pneumonia, viral pneumonia, acute pancreatitis, or a combination thereof in a subject, said method comprising administering to said subject a therapeutically effective amount of a corticosteroid and / or an immunosuppressant and an intracellular calcium signaling inhibitor, wherein said subject has a PaO2 / FiO2 (P / F) ratio of about 200 or less.

26. The intracellular calcium signaling inhibitor described in claim 25, wherein the therapeutically effective amounts of the corticosteroid and / or the immunosuppressant and the intracellular calcium signaling inhibitor are administered at different times.

27. ​​The intracellular calcium signaling inhibitor described in claim 25, wherein the therapeutically effective amounts of the corticosteroid and / or the immunosuppressant and the intracellular calcium signaling inhibitor are administered simultaneously.

28. An intracellular calcium signaling inhibitor as described in claim 25, wherein the ALI or ARDS includes respiratory failure.

29. The intracellular calcium signaling inhibitor described in claim 25, wherein the respiratory failure is mild respiratory failure indicated by a P / F ratio of 200 to 300, moderate respiratory failure indicated by a P / F ratio of 100 to 200, or severe respiratory failure indicated by a P / F ratio of less than 100.

30. The intracellular calcium signaling inhibitor described in claim 29, wherein a P / F ratio of less than 100 after two doses of the intracellular calcium signaling inhibitor indicates that the subject is a non-responder, and the subject receives up to six further doses in total.

31. The intracellular calcium signaling inhibitor described in claim 30, wherein the intracellular calcium signaling inhibitor is administered a total of up to six times.

32. The intracellular calcium signaling inhibitor of claim 25, wherein the corticosteroid is cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone, fludrocortisone acetate, deoxycorticosterone, deoxycorticosterone acetate, aldosterone, beclomethasone, or progesterone.

33. The immunosuppressant drug is cyclosporine, tacrolimus, sirolimus, everolimus, azathioprine, cyclophosphamide, methotrexate, mycophenolate, leflunomide, abatacept, adalimumab, alemtuzumab, anakinra, basilizimab, belimumab, bevacizumab, brodalumab, canakinumab, certolizumab, cetuximab, clazakizumab 26. The intracellular calcium signaling inhibitor of claim 25, which is not rituximab, sarilumab, vedolizumab, baricitinib, tofacitinib, or another Janus kinase inhibitor.

34. The intracellular calcium signaling inhibitor described in claim 25, wherein the immunosuppressant is a corticosteroid, glucocorticoid, anti-IL-6, immunomodulatory imide drug, 4-deoxypyridoxine, fingolimod, laquinimod, mizoribine, mycophenolic acid, pimecrolimus, tocilizumab, or voclosporin.

35. An intracellular calcium signaling inhibitor as described in claim 34, wherein the immunosuppressant is tocilizumab.

Images