Pancreatitis treatment

Abstract

To provide pharmaceuticals for improving pancreatitis symptoms in mammals including human.SOLUTION: Disclosed is a use of an inhibitor of intracellular calcium signaling in manufacture of a medicament for ameliorating human acute pancreatitis symptoms, where the symptoms are symptoms of acute pancreatitis, 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 or a pharmaceutically acceptable solvate thereof.SELECTED DRAWING: Figure 3A

Description

[Technical Field]

[0001] <Cross reference> This application claims the benefit of U.S. Provisional Patent Application No. 62 / 126,386, filed February 27, 2015, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Acute pancreatitis is the leading cause of gastrointestinal hospitalization and a major cost burden in the United States. Acute pancreatitis has a mortality rate of 10-25% in severely ill patients and 3-5% overall. There are currently no proven treatments available to victims of this disease. Summary of the Invention

[0003] Provided herein are embodiments relating to methods for ameliorating symptoms of pancreatitis in a mammal, such as a human. In other embodiments, described herein are methods for ameliorating symptoms of viral infection in a mammal, such as a human. In further embodiments, described herein are methods for ameliorating symptoms of T helper 17 cell (Th17)-induced inflammation and autoimmune disease.

[0004] In some embodiments, the method comprises identifying a human in need of amelioration of symptoms of pancreatitis and administering to the human an intracellular calcium signaling inhibitor at a dosage sufficient to ameliorate the symptoms. In other embodiments, the method comprises identifying a human in need of amelioration of symptoms of a viral disease and administering to the human an intracellular calcium signaling inhibitor at a dosage sufficient to ameliorate the symptoms. In further embodiments, the method comprises identifying a human in need of amelioration of symptoms of a Th17-induced disease and administering to the human an intracellular calcium signaling inhibitor at a dosage sufficient to ameliorate the symptoms. In some aspects, the intracellular calcium signaling inhibitor is a SOC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising a STIM1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising an Orai1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising an Orai2 protein.

[0005] In some embodiments, the intracellular calcium signaling inhibitor is a compound having the structure:

[0006] [ka] (collectively, "Compound A"), or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof. In some embodiments, the intracellular calcium signaling inhibitor is a compound having a structure from the group Compound A, or a nanoparticle formulation thereof, including a nanoparticle suspension or emulsion.

[0007] In some embodiments, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some embodiments, the intracellular calcium signaling inhibitor is the compound 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. In some embodiments, the intracellular calcium signaling inhibitor is the following compound (collectively "Compound A"): 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-2-yl)-2,4,6-trifluorobenzamide, 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-pyrazole) 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- 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-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl) In some embodiments, the symptom is selected from among N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, 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, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the symptom is a symptom of acute pancreatitis. In some embodiments, the symptom is inflammation and edema of the pancreas, upper abdominal pain radiating to the back, left upper abdominal pain radiating to the back, nausea, vomiting, vomiting worsened by eating, high heart rate, tachycardia, high respiratory rate, high blood pressure,Symptoms include at least one of: hypotension, dehydration, abdominal tenderness, fever, chills, peritonitis, hemodynamic instability, and reflex intestinal paralysis. In some embodiments, the symptoms are those of severe acute pancreatitis. In some embodiments, the symptoms include at least one of pancreatic necrosis and extrapancreatic organ damage. In some embodiments, the symptoms are those of chronic pancreatitis. In some embodiments, the symptoms include at least one of: persistent abdominal pain, digestive abnormalities, fat malabsorption, pain during feeding, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP inflammatory marker, decreased bicarbonate production, elevated fecal elastase level, elevated serum trypsinogen level, pancreatic calcification, elevated serum bilirubin level, and elevated alkaline phosphatase level. In some embodiments, the symptoms include at least one of elevated ESR level, elevated IgG4 level, elevated rheumatoid factor, presence of ANA antibody, presence of anti-smooth muscle antibody, or any assay that can identify chronic pancreatitis in humans. In some embodiments, the symptom includes at least one of steatorrhea, Sudan staining of fecal fat excretion of 7 grams or more of feces over 24 hours on a 100 g fatty meal, and fecal elastase levels in the fecal sample less than 200 μg / g. In some embodiments, the symptom includes at least one of abdominal pain, increased blood amylase levels, increased blood lipase levels, pancreatic enlargement, nausea, vomiting, internal bleeding, intestinal paralysis, fever, jaundice, weight loss, and increased heart rate. In some embodiments, the symptom includes elevated blood levels of amylase. In some embodiments, the symptom includes elevated blood levels of lipase. In some embodiments, the symptom includes a finding of necrosis by computed tomography (CT) scan. In some embodiments, the symptom includes premature digestive enzyme activation. In some embodiments, the premature digestive enzyme activation occurs in the human's pancreas. In some embodiments, the enzyme includes trypsin.

[0008] Some embodiments relate to methods of preventing or ameliorating symptoms associated with pancreatic disorders in humans at risk for pancreatic disorders. In some embodiments, the method comprises: identifying a human with risk factors associated with pancreatic disorders; and administering an intracellular calcium signaling inhibitor at a dosage sufficient to prevent or ameliorate the side effects. In some aspects, the intracellular calcium signaling inhibitor is a SOC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a compound having a structure from the Compound A group, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. 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. In some aspects, the pancreatic disorder comprises symptoms of acute pancreatitis. In some aspects, the pancreatic disorder comprises symptoms of chronic pancreatitis. In some embodiments, the human suffers from pancreatitis as a result of receiving a medication regimen comprising at least one of the following: corticosteroids, prednisolone, HIV medications, didanosine, pentamidine, diuretics, valproic acid, L-asparaginase, azathioprine, steroids such as estrogen, statins such as cholesterol-lowering statins, antihyperglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antidepressants, clozapine, risperidone, and olanzapine. In some embodiments, the human is identified as having a genetic form of pancreatitis. In some embodiments, the human has at least one mutant allele of trypsin 1 encoding trypsinogen, SPINK1 encoding trypsin inhibitor, and cystic fibrosis transmembrane conductance regulator.In some embodiments, the human suffers from pancreatitis as a result of at least one of high blood calcium, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic duct nonunion, congenital malformation of the pancreas, type 2 diabetes mellitus, pancreatic cancer, intraductal stones, vasculitis, inflammation of the microvessels in the pancreas, Coxsackievirus infection, and porphyria, such as acute intermittent porphyria and erythropoietic protoporphyria. In some embodiments, the human's physical condition is affected by at least one of gallstones, ethanol intoxication, alcoholism, trauma, mumps, an autoimmune disorder, a scorpion sting, hyperlipidemia, hypothermia, hyperparathyroidism, and endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid. In some embodiments, the human physical condition is affected by at least one of Coxsackievirus, cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella bacteria, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungi, roundworm parasites, Cryptosporidium cells, and Toxoplasma cells.

[0009] Some embodiments relate to methods for preventing or ameliorating symptoms associated with a viral disease in a human at risk for the viral disease. In some embodiments, the method comprises the steps of: identifying a human having risk factors associated with the viral disease; and administering an intracellular calcium signaling inhibitor at a dosage sufficient to prevent or ameliorate the side effects. Some embodiments relate to compositions for use in ameliorating symptoms of a viral disease in a human, comprising identifying a human in need of amelioration of symptoms of the viral disease and administering to the human an intracellular calcium signaling inhibitor at a dosage sufficient to ameliorate the symptoms. In some aspects, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising a STIM1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising an Orai1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising an Orai2 protein. In some aspects, the intracellular calcium signaling inhibitor is a compound having a structure from the group of Compound A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some embodiments, the intracellular calcium signaling inhibitor is the compound 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. In some embodiments, the intracellular calcium signaling inhibitor blocks the budding of a viral disease. In some embodiments, the viral disease is a hemorrhagic fever virus.In a further embodiment, hemorrhagic fever virus is Arenavirus, Filovirus, Bunyavirus, Flavivirus, Rhabdovirus, or combinations thereof.In a further embodiment, hemorrhagic fever virus is Ebola virus, Marburg virus, Lassa virus, Junin virus, Rotavirus, West Nile virus, Zika virus, Coxsackievirus, Hepatitis B virus, Epstein-Barr virus, Dengue virus, or Rift Valley virus.In some embodiments, symptom is fever or hemorrhagic diathesis.In a further embodiment, symptom of viral disease is at least one of facial flushing, chest flushing, petechiae, capillary leakage, bleeding, swelling, edema, hypotension, shock, fatigue, muscle pain, headache, vomiting, diarrhea, or combinations thereof.

[0010] Some embodiments relate to methods for preventing or ameliorating symptoms associated with a Th17-induced disease in a human at risk for the disease. In some embodiments, the method comprises: identifying a human with risk factors associated with a Th17-induced disease; and administering an intracellular calcium signaling inhibitor at a dosage sufficient to prevent or ameliorate the side effects. Some embodiments relate to compositions for use in ameliorating symptoms of a Th17-induced disease in a human, comprising identifying a human in need of amelioration of symptoms of pancreatitis and administering to the human an intracellular calcium signaling inhibitor at a dosage sufficient to ameliorate the symptoms. In some aspects, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising a STIM1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising an Orai1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising an Orai2 protein. In some aspects, the intracellular calcium signaling inhibitor is a compound having a structure from the group of Compound A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some embodiments, the intracellular calcium signaling inhibitor is the compound 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. In some embodiments, the intracellular calcium signaling inhibitor blocks Th17 cell differentiation. In some embodiments, the Th17-induced disease is a chronic inflammatory disease. In further embodiments, the chronic inflammatory disease is hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, or cancer.In other embodiments, the Th17-induced disease is an autoimmune disease. In further embodiments, the autoimmune disease is rheumatoid arthritis, lupus, celiac disease, psoriasis, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, or temporal arteritis. In some embodiments, the symptoms of Th17-induced disease are at least one of local redness, swelling, heat, pain, stiffness, fever, chills, fatigue, headache, or loss of appetite. In some embodiments, the symptoms occur in the human body, including the trunk, arms, hands, fingers, legs, feet, toes, head, neck, bones, joints, throat, sinuses, eyes, or a combination thereof.

[0011] Some embodiments relate to compositions comprising an intracellular calcium signaling inhibitor and at least one drug that negatively affects pancreatic activity. In some embodiments, the drug is selected from the list consisting of corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, valproic acid, L-asparaginase, azathioprine, steroids such as estrogen, statins such as cholesterol-lowering statins, antihyperglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antidepressants, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid. In some embodiments, the intracellular calcium signaling inhibitor is an SOC inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a compound having a structure from the group of Compound A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some embodiments, the intracellular calcium signaling inhibitor is the compound 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.

[0012] Some embodiments relate to a dosing regimen comprising administering to an individual a drug associated with a negative effect on pancreatic activity and an intracellular calcium signaling inhibitor. In some embodiments, the drug is selected from the list consisting of corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, valproic acid, L-asparaginase, azathioprine, steroids such as estrogen, statins such as cholesterol-lowering statins, antihyperglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antidepressants, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid. In some embodiments, the intracellular calcium signaling inhibitor is an SOC inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a compound having a structure from the group of Compound A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some embodiments, the intracellular calcium signaling inhibitor is the compound 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.

[0013] Some embodiments relate to compositions for use in ameliorating symptoms of pancreatitis in a human, comprising identifying a human in need thereof and administering to the human an intracellular calcium signaling inhibitor in a dosage sufficient to ameliorate the symptoms. In some aspects, the intracellular calcium signaling inhibitor is a SOC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising a STIM1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising an Orai1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel comprising an Orai2 protein. In some aspects, the intracellular calcium signaling inhibitor is a compound having a structure from the Compound A group, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. 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. In some embodiments, the intracellular calcium signaling inhibitor is the compound 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. In some embodiments, the composition further comprises an analgesic. In some embodiments, the analgesic comprises an opiate. In some embodiments, the analgesic comprises morphine. In some embodiments, the symptoms are those of acute pancreatitis. In some embodiments, the symptoms include at least one of pancreatic inflammation and edema, upper abdominal pain radiating to the back, left upper abdominal pain radiating to the back, nausea, vomiting, vomiting worsened by eating, high heart rate, tachycardia, high respiratory rate, hypertension, hypotension, dehydration, abdominal tenderness, fever, chills, peritonitis, hemodynamic instability, and reflex ileoplegia. In some embodiments, the symptoms are symptoms of severe pancreatitis.In some embodiments, the symptoms include at least one of pancreatic necrosis and extrapancreatic organ damage. In some embodiments, the symptoms are those of chronic pancreatitis. In some embodiments, the symptoms include at least one of persistent abdominal pain, digestive abnormalities, fat malabsorption, pain during feeding, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP inflammatory marker, decreased bicarbonate production, elevated fecal elastase level, elevated serum trypsinogen level, pancreatic calcification, elevated serum bilirubin level, and elevated alkaline phosphatase level. In some embodiments, the symptoms include at least one of elevated ESR level, elevated IgG4 level, elevated rheumatoid factor, presence of ANA antibody, presence of anti-smooth muscle antibody, or any assay that can identify symptoms of chronic pancreatitis in humans. In some embodiments, the symptoms include at least one of steatorrhea, Sudan staining of fecal fat excretion of 7 grams or more of feces over 24 hours on a 100 g fatty meal, and fecal elastase levels in the fecal sample of less than 200 μg / g. In some embodiments, the symptoms include at least one of abdominal pain, increased blood amylase levels, increased blood lipase levels, pancreatic enlargement, nausea, vomiting, internal bleeding, intestinal paralysis, fever, jaundice, weight loss, and increased heart rate. In some embodiments, the symptoms include premature digestive enzyme activation. In some embodiments, the premature digestive enzyme activation occurs in the human pancreas. In some embodiments, the enzyme includes trypsin.

[0014] Some embodiments relate to compositions for use in preventing or ameliorating symptoms associated with pancreatic disorder in a human at risk of pancreatic disorder, comprising the steps of: identifying a human with risk factors associated with pancreatic disorder; and administering an intracellular calcium signaling inhibitor at a dosage sufficient to prevent or ameliorate the side effects. In some embodiments, the intracellular calcium signaling inhibitor is an SOC channel inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a compound having a structure from the Compound A group, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, the pancreatic disorder comprises symptoms of acute pancreatitis. In some embodiments, the pancreatic disorder comprises symptoms of chronic pancreatitis. In some embodiments, the human receives a medication regimen comprising administration of at least one of a corticosteroid, prednisolone, an HIV medication, didanosine, pentamidine, a diuretic, valproic acid, L-asparaginase, azathioprine, a steroid such as an estrogen, a statin such as a cholesterol-lowering statin, an antihyperglycemic agent, metformin, a gliptin such as vildagliptin and sitagliptin, an atypical antidepressant, clozapine, risperidone, and olanzapine. In some embodiments, the human is identified as having a genetic form of pancreatitis. In some embodiments, the human has at least one mutant allele of trypsin 1, which encodes trypsinogen, SPINK1, which encodes a trypsin inhibitor, and cystic fibrosis transmembrane conductance regulator.In some embodiments, the human is afflicted with at least one of high blood calcium, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic duct nonunion, congenital malformation of the pancreas, type 2 diabetes mellitus, pancreatic cancer, intraductal stones, vasculitis, inflammation of the microvessels in the pancreas, Coxsackievirus infection, and porphyria, such as acute intermittent porphyria and erythropoietic protoporphyria. In some embodiments, the human's physical condition is affected by at least one of gallstones, ethanol intoxication, alcoholism, trauma, mumps, an autoimmune disorder, a scorpion sting, hyperlipidemia, hypothermia, hyperparathyroidism, and endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid. In some embodiments, the human physical condition is affected by at least one of cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella bacteria, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungi, roundworm parasites, Cryptosporidium cells, and Toxoplasma cells.

[0015] <Incorporated 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.

[0016] Among other things, PCT Application Publication No. WO2011 / 139489A2, published November 10, 2011, is incorporated herein by reference in its entirety, PCT Application Publication No. WO2009 / 035818, published March 19, 2009, is incorporated herein by reference in its entirety, PCT Application Publication No. WO2010 / 025295, published June 17, 2010, is incorporated herein by reference in its entirety, and PCT Application Publication No. WO PCT Application Publication No. WO2010 / 027875, published on July 28, 2011, is incorporated by reference herein in its entirety; PCT Application Publication No. WO2011 / 034962, published on July 28, 2011, is incorporated by reference herein in its entirety; PCT Application Publication No. WO2011 / 139489, published on January 26, 2012, is incorporated by reference herein in its entirety; PCT Application Publication No. WO2011 / 139765, published on March 8, 2012, is incorporated by reference herein in its entirety; PCT Application Publication No. WO2012 / 027710, published May 18, 2012, is incorporated herein by reference in its entirety, PCT Application Publication No. WO2012 / 170931, published February 21, 2013, is incorporated herein by reference in its entirety, PCT Application Publication No. WO2012 / 170951, published April 25, 2013, is incorporated herein by reference in its entirety, and PCT Application Publication No. WO2013 / 05 No. 9666, published on Apr. 25, 2013, is incorporated herein by reference in its entirety, PCT Application Publication No. WO2013 / 059677, published on Apr. 25, 2013, is incorporated herein by reference in its entirety, PCT Application Publication No. WO2014 / 043715, published on Mar. 20, 2014, is incorporated herein by reference in its entirety, and PCT Application Publication No. WO2014 / 059333, published on Apr. 17, 2014, is incorporated herein by reference in its entirety. [Brief explanation of the drawings]

[0017] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth embodiments in which the principles of the invention are utilized, and the accompanying drawings in which: [Figure 1A] 1 shows mouse acinar cell necrosis after treatment with TLCS. [Figure 1B] 1 shows human acinar cell necrosis after treatment with TLCS. [Figure 2A] 1 shows histopathological scores for caerulein-induced acute pancreatitis. [Figure 2B] 1 shows histopathological scores for TLCS-induced acute pancreatitis. [Figure 2C] Figure 1 shows the histopathological scores for FAEE-induced acute pancreatitis. [Figure 3A] 1 shows the IC50 measurement for N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide ("Compound I"). [Figure 3B] 1 shows the IC50 measurement for 2,6-difluoro-N-(1-(4-hydroxy-2-(trifluoromethyl)benzyl)-1H-pyrazol-3-yl)benzamide ("GSK-7975A"). [Figure 4A] Calcium uptake in the absence of CRAC inhibitors is shown. [Figure 4B] Figure 1 shows calcium uptake in the presence of a CRAC inhibitor. [Figure 5A] Calcium influx in the presence of the CRAC inhibitor Compound I. [Figure 5B] Calcium influx in the presence of the CRAC inhibitor GSK-7975A. [Figure 6A] Calcium influx in the absence of CRAC inhibitors is shown. [Figure 6B] Figure 1 shows the relative calcium influx in the presence of CRAC inhibitor Compound I and GSK-7975A compared to control. [Figure 7]The IC50 values ​​of Compound I against a number of cytokines are shown. [Figure 8A] Histopathological scores for various concentrations of Compound I are shown. [Figure 8B] The concentration of Compound I in the pancreas as a function of dose is shown. [Figure 9A] Serum amylase levels in non-induced (control) and induced acute pancreatitis mice with and without CRAC inhibitors. [Figure 9B] Serum lipase levels in non-induced (control) and induced acute pancreatitis mice with and without CRAC inhibitors are shown. [Figure 10] 1 shows the histopathological scores of therapeutically and prophylactically treated mice upon induction of acute pancreatitis. [Figure 11] TLCS-induced calcium levels are shown. [Figure 12] Mouse acinar cell amylase release levels are shown. DETAILED DESCRIPTION OF THE INVENTION

[0018] The methods and compositions disclosed herein are used to modulate intracellular calcium to ameliorate or prevent symptoms of pancreatitis. In some embodiments, the pancreatitis is acute pancreatitis. In some embodiments, the pancreatitis is chronic pancreatitis. In some embodiments, the methods and compositions disclosed herein are used to modulate intracellular calcium to ameliorate or prevent symptoms of a viral disease. In some embodiments, the viral disease is a hemorrhagic fever virus. In some embodiments, the hemorrhagic fever virus is an arenavirus, filovirus, bunyavirus, flavivirus, rhabdovirus, or a combination thereof. Hemorrhagic fever viruses include, but are not limited to, Ebola virus, Marburg virus, Lassa virus, Junin virus, rotavirus, West Nile virus, Zika virus, Coxsackievirus, Hepatitis B virus, Epstein-Barr virus, and the like. In further embodiments, the methods and compositions disclosed herein are used to modulate intracellular calcium to ameliorate or prevent symptoms of a Th17-induced disease. In some embodiments, the Th17-induced disease is an inflammatory disease. In further embodiments, the Th17-induced disease is an autoimmune disorder. In some embodiments, the compounds provided herein modulate SOC channel activity. In some embodiments, the methods and compounds provided herein modulate CRAC channel activity. In another embodiment, the compounds provided herein modulate STIM protein activity. In another embodiment, the methods and compounds provided herein modulate Orai protein activity. In another embodiment, the methods and compounds provided herein modulate the functional interaction between STIM and Orai proteins. In another embodiment, the methods and compounds provided herein reduce the number of functional SOC channels. 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 SOC channel blockers. In some embodiments, the methods and compounds described herein are CRAC channel blockers or CRAC channel modulators.

[0019] Calcium plays a critical role in cellular function and survival. For example, 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.

[0020] Virtually all cell types use cytoplasmic Ca in some way to regulate cellular function or to trigger specific responses. 2+ Depends on the generation of the signal. Cytoplasmic Ca 2+ Signals control many cellular functions, ranging from short-term responses such as contraction and secretion to longer-term regulation of cell growth and proliferation. Typically, such 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, which is coupled to phospholipase C (PLC) via a G protein mechanism. PLC activation leads to the generation of inositol 1,4,5-triphosphate (IP3), which in turn activates IP3 receptors to release Ca from the ER. 2+ This then causes the release of ER Ca 2+ The fall of ATP signals to activate store-operated calcium (SOC) channels in the plasma membrane.

[0021] Store-operated calcium (SOC) entry is a process that involves, but is not limited to, intracellular Ca 2+It is a process in cell physiology that regulates diverse functions such as replenishing ATP (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 several non-excitable cells, such as blood cells, immune cells, hematopoietic cells, T lymphocytes, mast cells, pancreatic acinar cells (PAC), epithelial and ductal cells of other glands (e.g., salivary glands), endothelial cells, and endothelial progenitor cells, SOC influx occurs via calcium release-activated calcium (CRAC) channels, a type of SOC channel.

[0022] The calcium entry mechanism has been termed store-operated calcium entry (SOCE). Stromal interaction molecule (STIM) proteins are essential components of SOC channel function, acting as sensors to detect calcium depletion from intracellular stores and to activate SOC channels.

[0023] <Calcium homeostasis> Intracellular calcium homeostasis is the result of the sum total of regulatory systems involved in controlling intracellular calcium concentration and movement. Intracellular calcium homeostasis is achieved, at least in part, within cells by calcium binding, by calcium movement to and from the plasma membrane, and by calcium movement across membranes of intracellular organelles, including, for example, the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria, and endocytic organelles, including endosomes and lysosomes.

[0024] The movement of calcium across the cell membrane is mediated by specialized proteins. For example, calcium from the extracellular space can enter the cell through various calcium channels and sodium / calcium exchangers, and is actively pumped out of the cell by calcium pumps and sodium / calcium exchangers. Calcium can also be released from internal stores through inositol triphosphate or ryanodine receptors and taken up by these organelles by calcium pumps.

[0025] Calcium can enter cells through any of a variety of common classes of calcium channels, including, but not limited to, voltage-gated calcium (VOC) channels, store-operated calcium (SOC) channels, and sodium / calcium exchangers that operate in the reverse mode. VOC channels are activated by membrane depolarization and are found in excitable cells such as nerves and muscles, and are largely absent from non-excitable cells. Under some conditions, Ca 2+ operates in reverse mode Na+-Ca 2+ It can enter cells via the exchanger.

[0026] Endocytosis provides another process by which cells can take up calcium from the extracellular medium through endosomes. In addition, some cells, such as exocrine cells, can release calcium via exocytosis.

[0027] Cytosolic calcium concentrations are tightly regulated in mammalian cells at resting levels usually estimated at approximately 0.1 μM, while extracellular calcium concentrations are typically approximately 2 mM. This tight regulation facilitates signal transduction into and within cells via transient calcium fluxes across the plasma membrane and organelle membranes. Cells contain a variety of intracellular calcium transport and buffering systems that are responsible for generating intracellular calcium signals and maintaining low resting cytosolic calcium concentrations. In resting cells, the primary components involved in maintaining basal calcium concentrations are calcium pumps and leak pathways in both the endoplasmic reticulum and the plasma membrane. Disruption of resting cytosolic calcium concentrations can affect calcium-dependent signal transmission and cause defects in many cellular processes. For example, cell proliferation is associated with the prolongation of calcium signaling sequences. Other cellular processes involved in calcium signaling include, but are not limited to, secretion, transcription factor signaling, and fertilization.

[0028] Cell surface receptors that activate phospholipase C (PLC) transport cytosolic Ca from intracellular and extracellular sources. 2+ Create a signal. [Ca 2+ The initial transient rise in intracellular calcium (i) is triggered by the release of Ca from the endoplasmic reticulum (ER) via the PLC product, inositol-1,4,5-trisphosphate (IP3), and the opening of IP3 receptors in the ER. 2+ This is due to the release of Ca across the plasma membrane (Streb et al. Nature, 306, 67-69, 1983). 2+ The later stage of influx occurs at the plasma membrane through specialized store-operated calcium (SOC) channels (in non-excitable cells such as immune PAC cells, the SOC channels are calcium release-activated calcium (CRAC) channels). 2+ Influx (SOCE) is Ca 2+ Ca at the plasma membrane so that emptying the store itself aids in store refilling. 2+SOCE is the process of activating the channel (Putney, Cell Calcium, 7, 1-12, 1986; Parekh et al., Physiol.Rev. 757-810; 2005). 2+ It not only provides calcium but also regulates 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)).

[0029] In lymphocytes and mast cells, activation of antigen or Fc receptors, respectively, in turn induces Ca release via CRAC channels in the plasma membrane. 2+ Ca influx from intracellular stores 2+ causes the release of intracellular Ca 2+The subsequent rise in NFAT activates calcineurin, a phosphatase that regulates the transcription factor NFAT. In quiescent cells, NFAT is phosphorylated and present in the cytoplasm; upon dephosphorylation by calcineurin, NFAT translocates to the nucleus and activates different gene programs depending on the stimulus conditions and cell type. In response to infection and during transplant rejection, NFAT pairs with the transcription factor AP-1 (Fos-Jun) in the nuclei of "effector" T cells, thereby transactivating cytokine genes, genes that regulate T cell proliferation, and genes that orchestrate an active immune response (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 autoimmune responses (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).

[0030] The endoplasmic reticulum (ER) carries out various processes. 2+ Sink and agonist-sensitive Ca 2+ In the latter case, the lumen acts as both a calcium store and a calcium ion store, while protein folding / processing occurs within the lumen. 2+Dependent chaperone proteins ensure that newly synthesized proteins are correctly folded and delivered to their appropriate destination. The ER is also involved in vesicle trafficking, release of stress signals, regulation of cholesterol metabolism, and apoptosis. Many of these processes are mediated by intraluminal Ca. 2+ Protein misfolding, ER stress response, and apoptosis all require prolonged Ca 2+ It can be induced by depletion of the ER. 2+ Because it contains ER Ca 2+ The contents of Ca 2+ However, to preserve the functional integrity of the ER, Ca 2+ It is important that the Ca content does not fall too low, or at least is maintained at a low level. 2+ Replenishment of the ER by ER Ca is a central process for all eukaryotic cells. 2+ A decrease in the content of store-operated Ca 2+ This Ca 2+ A key function of the entry pathway is the regulation of ER Ca, which is required for proper protein synthesis and folding. 2+ However, store-operated Ca 2+ Channels have other important roles.

[0031] Our understanding of store-operated calcium entry is based on the idea that the store-emptying process is a Ca 2+ Release activated Ca 2+ Ca current in mast cells, called ICRAC 2+ This was confirmed by electrophysiological studies, which confirmed that ICRAC is a voltage-inactivated, inwardly rectifying, Ca current. 2+ It is found in a variety of cell types, primarily of hemapoietic origin. ICRAC is not the only store-operated current, and at present, store-operated influx is a Ca current with different properties in different cell types.2+ It is clear that ICRAC encompasses a family of store-operated Ca permeable channels. 2+ current and remains a popular model for studying store-operated influx.

[0032] Store-operated calcium channels transport ER Ca 2+ It can be activated by any store-emptying procedure; it is not thought to matter how the stores are emptied; the net effect is store-operated Ca 2+ Physiologically, emptying stores involves the activation of IP3 or other Ca influx. 2+ Increased levels of Ca release signal subsequently releases Ca from stores 2+ However, there are various other ways to empty the stores. These include: 1) Elevation of IP3 in the cytosol (after receptor stimulation or dialysis of the cytosol with IP3 itself or related analogues such as the non-metabolizable analog Ins(2,4,5)P3); 2) Ca permeabilizes the ER membrane 2+ application of ionophores (e.g., ionomycin); 3) Ca leaks out of the store, thus preventing the store from refilling. 2+ High concentrations of Ca, which chelates 2+ dialysis of the cytoplasm with a chelating agent (e.g., EGTA or BAPTA); 4) Sarcoplasmic / endoplasmic reticulum Ca2+ receptors such as thapsigargin, cyclopiazonic acid, and di-tert-butylhydroquinone 2+ -Exposure to ATPase (SERCA) inhibitors; 5) Sensitization of IP3 receptors to resting levels of InsP3 by drugs such as thimerosal; and 6) Membrane-permeable metal Ca such as N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) 2+ Direct loading of chelating agents into the store. Through mass action, TPEN stores total Ca 2+ without changing the free luminal Ca2+ The concentration is reduced, thereby generating a signal that depends on store depletion.

[0033] Such methods of emptying stores are not without potential problems. 2+ An important function of influx is the Ca in stores. 2+ A decrease in the cytoplasmic Ca content activates the channel. 2+ However, ionomycin and SERCA pump blockers usually induce a subsequent increase in cytosolic Ca as a result of store depletion. 2+ Ca concentration rises, 2+ The increase in Ca 2+ Permeable to Ca 2+ One way to circumvent this problem is to use high concentrations of Ca with EGTA or BAPTA. 2+ Chelating agents induce cytoplasmic Ca 2+ The key is to use the drug under strongly buffered conditions.

[0034] Store-operated calcium entry A decrease in calcium concentration in intracellular calcium stores, such as the endoplasmic reticulum, resulting from calcium release from intracellular calcium stores, provides a signal for calcium entry into the cell from the extracellular medium. This calcium entry results in a sustained "plateau" increase in cytosolic calcium concentration and is generally independent of voltage-gated plasma membrane channels and does not involve calcium-mediated activation of calcium channels. This calcium entry mechanism is termed capacitative calcium entry (CCE), calcium release-activated, store-sensitive, or depletion-operated calcium entry. Store-operated calcium entry can be recorded as an ionic current with unique properties. This current is called I SOC (store-sensitive current) or I CRAC (calcium release activated current).

[0035] Electrophysiological analysis of store-operated or calcium release-activated currents has revealed distinct biophysical properties of these currents (see, e.g., Parekh and Penner (1997) Physiol. Rev. 77:901-930). For example, the currents can be activated by depletion of intracellular calcium stores (e.g., by nonphysiological activators such as thapsigargin, CPA, ionomycin, and BAPTA, as well as physiological activators such as IP3), are selective for divalent cations such as calcium over monovalent ions in physiological solutions or conditions, are affected by changes in cytoplasmic calcium concentration, and can exhibit altered selectivity and conductance in the presence of low extracellular concentrations of divalent cations. The currents can also be blocked or potentiated (depending on the concentration) by 2-APB, can be blocked by SKF96365 and Gd3+, and can generally be described as calcium currents that are not strictly voltage-gated.

[0036] Patch clamp studies in mast cells and Jurkat leukemic T cells have established the CRAC influx mechanism as an ion channel with unique biophysical characteristics, which are Ca2+-coupled with very low conductivity. 2+ Furthermore, CRAC channels have been shown to meet stringent criteria for being store-operated, which means that they are not simply selective for cytosolic Ca 2+ or other messengers generated by PLC, rather than Ca in the ER. 2+ This activation is due to a decrease in the amount of ATP (Prakriya et al., In Molecular and Cellular Insights into Ion Channel Biology (ed. Robert Maue) 121-140 (Elsevier Science, Amsterdam, 2004)).

[0037] <Regulation of store-operated calcium entry by intracellular calcium stores> Store-operated calcium entry is regulated by the level of calcium 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. Different cells have been studied to characterize intracellular calcium stores, 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) (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).

[0038] Accumulation of calcium within storage organelles, the endoplasmic reticulum and sarcoplasmic reticulum (SR; a specialized version of the endoplasmic reticulum in striated muscle), is achieved via the sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA), commonly referred to as the calcium pump. During signal transduction (i.e., when ER channels are activated, resulting in calcium release from the ER to the cytoplasm), ER 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).

[0039] Calcium release channels associated with IP3 and ryanodine receptors mediate the controlled release of calcium from the endoplasmic reticulum and sarcoplasmic reticulum into the cytoplasm as a result of transient increases in cytoplasmic calcium concentration. IP3 receptor-mediated calcium release is triggered by IP3 formed by the breakdown of plasma membrane phosphoinositides via the action of phospholipase C, which is activated by agonist binding 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 regulated by cyclic ADP-ribose.

[0040] Thus, calcium concentrations in stores and the cytoplasm fluctuate. For example, ER free calcium concentrations can decrease from 60-400 μM to approximately 1-50 μM when HeLa cells are treated with histamine, an agonist of PLC-linked histamine receptors (Miyawaki et al. (1997) Nature 388:882-887). A decrease in the free calcium concentration in intracellular stores activates store-operated calcium entry. Thus, depletion of store calcium, as well as a concomitant increase in cytosolic calcium concentration, can regulate store-operated calcium entry into cells.

[0041] <Buffering of cytoplasmic calcium> Agonist activation of signaling processes in cells can be associated with a dramatic increase in the calcium permeability of the endoplasmic reticulum across the plasma membrane, for example, via the opening of IP3 receptor channels and store-operated calcium entry. This increase in calcium permeability is 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, which is a sustained increase in calcium concentration resulting from calcium influx into the cytoplasm from the extracellular medium. Following stimulation, the resting intracellular free calcium concentration of approximately 100 nM can increase globally to greater than 1 μM and even higher in cellular microdomains. Cells regulate these calcium signals through endogenous calcium buffers, including physiological buffering by organelles such as mitochondria, the endoplasmic reticulum, and the Golgi. Mitochondrial uptake of calcium via uniporters in the inner membrane occurs due to a large negative mitochondrial membrane potential, and accumulated calcium is slowly released by sodium-dependent and sodium-independent exchangers and, under some conditions, the permeability transition pore (PTP). Thus, mitochondria can act as calcium buffers by taking up calcium during cellular activation and slowly releasing it later. Calcium uptake into the endoplasmic reticulum is regulated by sarcoplasmic and endoplasmic reticulum calcium ATPase (SERCA). Calcium uptake into the Golgi is mediated by P-type calcium transporting ATPase (PMR1 / ATP2C1). Additionally, there is evidence that a significant amount of calcium released after IP3 receptor activation is extruded from the cell by the action of plasma membrane calcium ATPase. For example, plasma membrane calcium ATPase provides the predominant mechanism for calcium removal in human T cells and Jurkat cells, although sodium / calcium exchange also contributes to calcium removal in human T cells. Within calcium-storing organelles, calcium ions can bind to specialized calcium-buffering proteins, such as calsequestrin, calreticulin, and calnexin.Additionally, 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 by which cytosolic calcium concentrations may be reduced are proteins related to, involved in, and / or provide for cytosolic calcium buffering. Thus, cytosolic calcium buffering is defined as the release of slow calcium influx through the SO2 channel, or Ca. 2+ During the burst of release, cytoplasmic Ca 2+ Helps regulate cytoplasmic Ca levels 2+ An increase in the level, or store refill, inactivates SOCE.

[0042] Downstream calcium influx-mediated events In addition to intracellular changes in calcium stores, store-operated calcium entry affects multiple events due to, or in addition to, changes in store sensitivity. For example, Ca 2+ Influx results in the activation of many calmodulin-dependent enzymes, including the serine phosphatase calcineurin. Activation of calcineurin by increased intracellular calcium results in acute secretory processes such as mast cell degranulation. Activated mast cells release preformed granules containing histamine, heparin, TNFα, and enzymes such as β-hexosaminidase. Several cellular events, such as B and T cell proliferation, require sustained calcineurin signaling, which requires sustained increases in intracellular calcium. Many transcription factors are regulated by calcineurin, including NFAT (nuclear factor of activated T cells), MEF2, and NFκB. NFAT transcription factors play important roles in many cell types, including immune cells. In immune cells, NFAT mediates the transcription of many molecules, including cytokines, chemokines, and cell surface receptors. Transcription elements for NFAT 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 (TNFα), granulocyte colony-stimulating factor (G-CSF), and gamma-interferon (γ-IFN).

[0043] The activity of NFAT proteins is regulated by their phosphorylation level, which in turn is regulated by both calcineurin and NFAT kinase. Activation of calcineurin by an increase in intracellular calcium concentration results in the dephosphorylation of NFAT and its entry into the nucleus. Rephosphorylation of NFAT masks the nuclear localization sequence of NFAT, preventing it from entering the nucleus. Due to its strong dependence on calcineurin-mediated dephosphorylation for localization and activity, NFAT is a sensitive indicator of intracellular free calcium levels.

[0044] <Calcium channel inhibitors> Disclosed herein are numerous calcium channel inhibitors that are consistent with the methods, compositions, administration regimens, and compositions for use disclosed herein. In some embodiments, the calcium channel inhibitor is a SOC inhibitor. In some embodiments, the calcium channel inhibitor is a CRAC inhibitor. In some embodiments, the calcium channel inhibitor inhibits channels comprising the STIM1 protein. In some embodiments, the calcium channel inhibitor inhibits channels comprising the Orai1 protein. In some embodiments, the calcium channel inhibitor inhibits channels comprising the Orai2 protein.

[0045] In some embodiments, the compound has the structure:

[0046] [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 the compound 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. In some embodiments, the intracellular calcium signaling inhibitor is selected from the group consisting of the following compounds: 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-2-yl)-2,4,6-tri ...-1H-pyrazol-5-yl)-2,4,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1H-pyrazol-5- Benzamide, 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-difluorobenz Amide, 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- N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 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-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro- The compound is selected from among 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-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, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0047] Calcium Signaling and Pancreatic Health Calcium signaling is central to the activity of a healthy pancreas. Food stimulates the release of acetylcholine (ACh) and cholecyctokinin (CCK), which interact with phospholipase C (PLC)-linked receptors on pancreatic acinar cells (PACs). In healthy PACs, ACh or CCK receptors trigger the formation of IP3, 1,4,5-inositol triphosphate, which spreads to the apical region and releases Ca in a controlled, pulsatile manner. 2+ It stimulates IP3 receptors on the endoplasmic reticulum (ER) to release Ca. 2+ Vibration stimulates the release of proenzymes into the pancreatic duct. Over time, ER Ca 2+ needs to be replenished, which is achieved by gentle activation of CRAC channels in the basolateral region of the cell.

[0048] In certain situations (e.g., alcoholism or excessive drinking, gallstones, etc.), fatty acid ethyl esters (FAEEs) formed from alcohol or bile acids accumulated by gallstones diffuse into the PAC. Inside the PAC, FAEEs and bile acids are transported to the ER Ca2+ receptor via activation of IP3 receptors. 2+ Overstimulation of CCK receptors also induces a robust release of Ca from ER stores. 2+ Ca release can be induced. 2+ Emptying the stores leads to hyperactivation of CRAC channels, which in turn allows Ca 2+ This causes excessive influx of Ca. 2+The influx causes the release of enzymes from zymogen granules and the inappropriate activation of intracellular trypsin, which itself subsequently activates other pancreatic digestive enzymes, resulting in pancreatic autodigestion and necrosis, which can be blocked by CRAC channel inhibitors such as Compound I, GSK-7975A, N-(5-(2,5-dimethylbenzo[d]oxazol-6-yl)thiazol-2-yl)-2,3,6-trifluorobenzamide (Compound II), or 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide (Compound III).

[0049] If left unaddressed, inappropriate release and activation of digestive enzymes such as trypsin from zymogen granules can lead to autolysis of pancreatic cells, resulting in pancreatitis. As discussed above, acute or chronic pancreatitis can have substantial negative effects on an individual's health.

[0050] <Symptoms and causes of pancreatitis> Acute or chronic pancreatitis is associated with severe, burning pain in the upper or left upper abdomen that radiates to the back, nausea, and vomiting that worsens with eating. Depending on the severity of the illness, internal bleeding may also occur. Blood pressure, heart rate, and respiratory rate are frequently elevated, but dehydration can lead to a decrease in blood pressure rather than an increase. The abdomen is frequently tender, but the pain is less severe than pain in the pancreas itself. Reflex bowel paralysis is commonly seen in cases of pancreatitis, and fever or jaundice is not uncommon. Common symptoms and signs of pancreatitis include severe upper abdominal pain (epigastric pain) that radiates to the back, nausea, vomiting, loss of appetite, fever, chills (shivering), hemodynamic instability (including shock), tachycardia (rapid heartbeat), respiratory distress, and peritonitis.

[0051] Less commonly observed symptoms that indicate severe disease are the many medical "signs" of severe abdominal distress: Gray-Turner sign (hemorrhagic discoloration of the flank), Cullen sign (hemorrhagic discoloration of the umbilicus), pleural effusion (fluid in the base of the pleural cavity), Grunwald sign (the appearance of ecchymosis and large bruises around the umbilicus due to localized toxic lesions of the blood vessels), Korte sign (pain or swelling in the area where the head of the pancreas is located (epigastrium, i.e., 6-7 cm above the umbilicus)). Resistance), Kamenchik's sign (pain with pressure below the xiphoid process), Mayo-Robson's point (a point on the border of the internal two-thirds with the external one-third of the line representing the bisection of the left upper abdomen, where tenderness to pressure is present in pancreatic disease. At this point, the tail of the pancreas protrudes above the abdominal wall), etc. Mayo-Robson's sign (pain on pressure lateral to the erector spinae, and at the top of the left 12th rib (left inferior vertebral angle (CVA)).

[0052] A person suffering from pancreatitis may demonstrate some, all, or few to none of the above symptoms. In some cases, abdominal pain may be the only symptom of the disease.

[0053] Chronic pancreatitis can lead to diabetes or pancreatic cancer. Defects in the delivery of digestive enzymes such as trypsin can lead to poor digestion, which can lead to weight loss.

[0054] As many as 80 percent of cases of pancreatitis are caused by alcohol and gallstones. Gallstones are one of the most common causes of acute pancreatitis. Alcohol is one of the most common causes of chronic pancreatitis.

[0055] However, in addition to alcohol and gallstones, there are many additional causes of pancreatitis. Some medications may also be associated with pancreatitis. Examples of medications associated with pancreatitis include corticosteroids such as prednisolone, HIV medications such as didanosine and pentamidine, diuretics, anticonvulsants such as valproic acid, chemotherapy drugs such as L-asparaginase and azathioprine, estrogens, drugs that increase blood triglycerides, statins such as cholesterol-lowering statins, antihyperglycemic drugs such as metformin, and gliptins such as vildagliptin, sitagliptin, saxagliptin, and linagliptin, tetracyclines, sulfonamides, azathioprine, mercaptopurine, pentamidine, glimethoprim-sulfamethoxazole, and salicylates. In some cases, medications used to treat diseases associated with increased incidence of pancreatitis may also be incidentally associated with pancreatitis. Examples include statins in dyslipidemia and gliptins in diabetes. In addition, some atypical antipsychotics, such as clozapine, risperidone, and olanzapine, may also cause pancreatitis. This list is not exhaustive.

[0056] Non-pharmacological causes of pancreatitis are also known. For example, hereditary forms of pancreatitis are known to result in the activation of trypsinogen in the pancreas, causing autodigestion. Genes associated with hereditary pancreatitis include Trypsin1, which encodes trypsinogen; SPINK1, which encodes trypsin inhibitor; and cystic fibrosis transmembrane conductance regulator.

[0057] Other common non-medicinal causes of pancreatitis include trauma, parotitis, autoimmune disease, hypercalcemia, hypothermia, and previous endoscopic retrograde cholangiopancreatography (ERCP). Pancreatic ductal nonunion is a common congenital anomaly of the pancreas that may underlie some recurrent cases. Penetrating ulcers are also associated with pancreatitis. Type 2 diabetes is associated with a 2.8-fold increased risk of developing pancreatitis. Additional diseases associated with pancreatitis include pancreatic cancer, intraductal stones, vasculitis (inflammation of the small blood vessels in the pancreas), coxsackievirus infection, and porphyrias, particularly acute intermittent porphyria and erythropoietic protoporphyria. Pregnancy is also associated with pancreatitis in some cases. Repeated marathon running, anorexia, and bulemia, as well as fat necrosis, cystic fibrosis, and scorpion venom, are also implicated in some cases of pancreatitis.

[0058] Many infectious agents are associated with pancreatitis, including viral infections with viruses such as cytomegalovirus, hepatitis B, herpes simplex virus, mumps rubra virus, and varicella-zoster virus, among others; bacterial infections with bacteria such as Legionella, Leptospira, Mycoplasma, or Salmonella; fungal infections with fungi such as those of the genus Aspergillus; or parasitic infections with nematodes of the genus Roundworm, or with Apicomplexa alveolata, Cryptosporidium, and Toxoplasma.

[0059] The medical student memory aid "GETSMASHED" is frequently used to remember some of the common causes of pancreatitis: G - gallstones, E - ethanol, T - trauma, S - steroids, M - mumps, A - autoimmune pancreatitis, S - scorpion sting, H - hyperlipidemia, hypothermia, hyperparathyroidism, E - endoscopic retrograde cholangiopancreatography, D - drugs (commonly azathioprine, valproate).

[0060] Pancreatitis can also be idiopathic, in which case no cause is identified.

[0061] <Classification of pancreatitis> Pancreatitis, particularly acute pancreatitis, is frequently classified as "mild," "moderate," or "severe," depending on the primary response to cellular injury. All of these classifications are characterized by the misactivation of pancreatic enzyme precursors, such as trypsinogen, within the pancreas, usually through colocalization with the trypsinogen maturation enzyme cathepsin, which activates trypsinogen to trypsin. All three classifications are characterized by pancreatic inflammation and edema. Moderate and severe pancreatitis are further characterized by pancreatic necrosis and secondary damage to extrapancreatic organs; patients with moderate acute pancreatitis suffer from transient (<48 hours) organ failure, while patients with severe acute pancreatitis suffer from persistent (>48 hours) organ failure.

[0062] In response to the aforementioned problems, the pancreas may directly synthesize inflammatory mediators such as TNF-α and IL-1, or otherwise activate the immune system, in association with the inflammatory response and recruitment of neutrophils to the pancreas, or due to necrosis and leakage of cellular components. The inflammatory response may also lead to secondary symptoms of pancreatitis, such as hypovolemia from capillary permeability, acute respiratory distress syndrome, disseminated intravascular coagulation, renal failure, cardiovascular failure, and gastrointestinal bleeding.

[0063] Acute pancreatitis (acute hemorrhagic pancreatic necrosis) is further characterized by acute inflammation and necrosis of the pancreatic parenchyma, enzymatic necrosis of pancreatic fatty lesions, and vascular necrosis (hemorrhage) resulting from intrapancreatic activation of pancreatic enzymes. Lipase activation can also result in necrosis of adipose tissue in the pancreatic interstitium and peripancreatic space, as well as vascular injury. Digestion of the vascular wall results in thrombosis and hemorrhage. The inflammatory infiltrate is rich in neutrophils. Due to the pancreas lacking a capsule, inflammation and necrosis can extend to involve the fascial layer in the immediate vicinity of the pancreas.

[0064] Chronic pancreatitis is persistent inflammation of the pancreas that alters the normal organization and function of the organ. Chronic pancreatitis may be associated with episodes of acute pancreatitis, persistent abdominal pain, or digestive defects. Patients with chronic pancreatitis usually demonstrate persistent abdominal pain or malabsorption of dietary fat. Pain during food intake, especially with fatty or high-protein foods, is common. Weight loss due to malabsorption of food or reduced food intake due to discomfort is also common.

[0065] A common complication of chronic pancreatitis is diabetes.

[0066] Alcoholism, smoking, malnutrition, trauma, hypercalcemia, calcified stones, cystic fibrosis, and genetic defects in trypsinogen processing and stability are commonly associated with chronic pancreatitis.

[0067] Chronic pancreatitis is typically diagnosed based on examination of pancreatic structure and function. Serum amylase and lipase may or may not be moderately elevated in cases of chronic pancreatitis due to uncertain levels of germ cell damage. Lipase elevation is the more likely of the two to be found. Amylase and lipase are almost always found elevated in acute disease, along with elevated CRP inflammatory markers that broadly follow the severity of the disease.

[0068] The secretin stimulation test is perhaps the most accurate functional test for diagnosing chronic pancreatitis. It uses impaired bicarbonate production early in chronic pancreatitis to identify individuals with early stages of the disease (95% sensitivity). Additional tests used to determine chronic pancreatitis are fecal elastase measurements in the stool, serum trypsinogen, computed tomography (CT), ultrasound, EUS, MRI, ERCP, and MRCP. Pancreatic calcifications may be seen on abdominal X-rays as well as CT scans. However, notably, ERCP and X-rays can precipitate acute pancreatitis.

[0069] Many additional tests are available to assay for chronic pancreatitis. Elevated serum bilirubin and alkaline phosphatase levels indicate chronic pancreatitis and, in some cases, common bile duct stricture due to edema, fibrosis, or cancer. Autoimmune-related chronic pancreatitis is accompanied by elevated ESR, IgG4, rheumatoid factor, ANA, and anti-smooth muscle antibodies, any of which assays may indicate chronic pancreatitis in humans. The classic symptom of chronic pancreatitis, i.e., steatorrhea or food malabsorption, may be diagnosed by two different studies: Sudan chemical staining of fecal or fecal fat excretion of 7 grams or more over a 24-hour period on a 100-gram fatty meal. To check for exocrine pancreatic dysfunction, a typical sensitive and specific test is fecal elastase measurement performed on a single fecal sample; values ​​below 200 μg / g indicate pancreatic insufficiency.

[0070] Many methods are known for assessing the severity of human pancreatitis. Common tests include BISAP, Ranson's, APACHE-II, and CTSI. The BISAP test, for example, is based on the following criteria assessed within the first 24 hours after admission: blood urea nitrogen >25 mg / dL (8.92 mmol / L); impaired mental status, defined as disorientation, lethargy, somnolence, coma, or stupor; ≥2 systemic inflammatory response syndrome criteria; age >60; and the presence of pleural effusion. A positive assessment of any of these criteria results in a "point" in the total score, ranging from 0 to 5. In some embodiments of the test, mortality rates ranged from less than 1% in the lowest-risk group to over 20% in the highest-risk group.

[0071] Many references discuss testing for pancreatitis severity, each of which is incorporated herein by reference: Wu BU, Johannes RS, Sun X, Tabak Y, Conwell DL, Banks PA. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut. 2008 Dec; 57(12):1698-703. doi: 10.1136 / gut.2008.152702. Epub 2008 Jun 2. PubMed PMID: 18519429; Papachristou GI, Muddana V, Yadav D, O'Connell M, Sanders MK, Slivka A, Whitcomb DC. Comparison of BISAP, Ranson's, APACHE-II, and CTSI scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J Gastroenterol. 2010 Feb; 105(2):435-41; quiz 442. doi: 10.1038 / ajg.2009.622. Epub 2009 Oct 27. PubMed PMID: 19861954; and Gompertz M, Fernandez L, Lara I, Miranda JP, Mancilla C, Berger Z. [Bedside index for severity in acute pancreatitis (BISAP) score as predictor of clinical outcome in acute pancreatitis: retrospective review of 128 patients]. Rev Med Chil. 2012 Aug; 140(8):977-83. doi: 10.1590 / S0034-98872012000800002. Spanish. PubMed PMID: 23282769.

[0072] <Improvement in the treatment of pancreatitis> Disclosed herein are compositions and methods for therapeutic amelioration of pancreatitis and its symptoms, such as through administration of a calcium channel inhibitor, such as a CRAC inhibitor. In some embodiments, the pancreatitis is acute pancreatitis. In some embodiments, the pancreatitis is chronic pancreatitis. In some embodiments, methods for ameliorating symptoms of pancreatitis in a human are disclosed. In some embodiments, methods for ameliorating symptoms of pancreatitis in a human are disclosed, the methods comprising identifying a human in need of amelioration of symptoms of pancreatitis and administering to the human an intracellular calcium signaling inhibitor at a dosage sufficient to ameliorate the symptoms.

[0073] The human may be identified using a common test for symptoms of pancreatitis, such as, for example, BISAP, Ranson's, APACHE-II, and CTSI. The test may be BISAP. The test may be Ranson's. The test may be APACHE-II. The test may be CTSI. In some embodiments, the human is identified as being in need of improvement in symptoms of pancreatitis by having a BISAP score of 5, 4, 3, 2, or 1. In some embodiments, the human is identified as having a BISAP score of 2. In some embodiments, the human is identified as having a BISAP score of 3. In some embodiments, the human is identified as having a BISAP score of 4. In some embodiments, the human is identified as having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 symptoms of pancreatitis, such as the symptoms of pancreatitis disclosed herein. In some embodiments, rather than being a human, the subject is a non-human mammal.

[0074] In some embodiments, the symptoms are symptoms of acute pancreatitis. In some embodiments, the symptoms are symptoms of chronic pancreatitis.

[0075] Symptoms may include at least one of abdominal pain, increased blood amylase levels, increased blood lipase levels, pancreatic enlargement, nausea, vomiting, internal bleeding, intestinal paralysis, fever, jaundice, weight loss, and increased heart rate. Symptoms may include premature digestive enzyme activation. Premature digestive enzyme activation may occur, for example, in the human pancreas. In some embodiments, the enzyme includes trypsin.

[0076] In some embodiments, the intracellular calcium signaling inhibitor is a SOC channel inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some embodiments, the CRAC channel inhibitor comprises Compound I. In some embodiments, the CRAC channel inhibitor comprises GSK-7975A. In some embodiments, the CRAC channel inhibitor comprises Compound II. In some embodiments, the CRAC channel inhibitor comprises Compound III. In some embodiments, ameliorating the symptoms of pancreatitis further comprises administering an analgesic drug. In some embodiments, ameliorating the symptoms of pancreatitis further comprises administering an analgesic drug comprising an opiate. In some embodiments, ameliorating the symptoms of pancreatitis further comprises administering an analgesic drug comprising morphine. In some embodiments, ameliorating the symptoms of pancreatitis further comprises administering an analgesic drug comprising fentanyl. In some embodiments, ameliorating the symptoms of pancreatitis further comprises administering an analgesic drug comprising tramadol. In some embodiments, ameliorating the symptoms of pancreatitis further comprises administering an analgesic drug comprising meperidine.

[0077] In some embodiments, the intracellular calcium signaling inhibitor has an in vitro IC determined for the compound. 50 In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration equal to, similar to, or higher than the in vitro IC value determined for the compound. 50Values ​​of 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, 5 to achieve a tissue level concentration that is 7x, 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 from 1x to 100x.

[0078] In some embodiments, the calcium signaling inhibitor has an in vitro IC determined for the compound. 50 Delivered to achieve tissue level concentrations ranging from 1x to 100x, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x, 7x to 43x, 8x to 43x, 9x to 41x, or 10x to 40x of the value, or any non-integer number within said ranges.

[0079] In some embodiments, the calcium signaling inhibitor is at least 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, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM, 40 μM, 41 μM, 42 μM, μM, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM M, 40μM, 41μM, 42μM, 43μM, 44μM, 45μM, 46μM, 47μM, 48μM, 49μM, 50μM, 51μM, 52μM, 53μM, 54μM, 55μM, 56μM, 57μM, 58μM, 59μM, 60μM, 61μM, 62μM, 63μM, 64μM, 65μM, 66μM, 67μM, 6 8μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, 82 95 μM, 96 μM, 97 μM, 98 μM, 99 μM, 100 μM, or any non-integer multiple ranging from about 1 μM to about 100 μM, delivered to achieve tissue level concentrations.

[0080] In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration ranging from 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 said ranges.

[0081] In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration ranging from 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 said ranges.

[0082] In some embodiments, amelioration of pancreatitis includes a reduction in the severity of at least one symptom of pancreatitis. In some embodiments, amelioration of pancreatitis includes a reduction in the severity of at least one symptom of pancreatitis such that the symptom no longer affects a previously affected person. In some embodiments, amelioration includes a reduction in at least one symptom such that the symptom no longer affects a previously affected person. In some embodiments, amelioration includes a 10%, 20%, 30%, 40%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% reduction in the symptom. In some embodiments, the improvement comprises a reduction in the severity of multiple symptoms, such as 2, 3, 4, 5, 6, 7, 8, 9, or up to more than 9 symptoms, including all symptoms, and the reduction comprises a 10%, 20%, 30%, 40%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% reduction in the symptoms.

[0083] In some embodiments, amelioration includes halting the progression of pancreatitis, such as acute pancreatitis or chronic pancreatitis, hi some embodiments, amelioration includes halting the progression of pancreatitis, such as acute pancreatitis or chronic pancreatitis, so that more severe symptoms, such as organ failure, pancreatic necrosis, or death, do not occur.

[0084] <Preventive improvement of acute and chronic pancreatitis> Disclosed herein are compositions and methods for the prophylactic amelioration of acute pancreatitis and its symptoms, such as through the administration of a calcium channel inhibitor, such as a CRAC inhibitor. In some embodiments, methods for ameliorating symptoms of pancreatitis in a human are disclosed. In some embodiments, methods for ameliorating symptoms of pancreatitis in a human are disclosed, the methods comprising identifying a human in need of prophylactic amelioration of symptoms of pancreatitis, and administering to the human an intracellular calcium signaling inhibitor in a dosage sufficient to prophylactically ameliorate the symptoms.

[0085] In some embodiments, the intracellular calcium signaling inhibitor is an SOC channel inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some embodiments, the CRAC channel inhibitor comprises Compound I. In some embodiments, the CRAC channel inhibitor comprises GSK-7975A. In some embodiments, the CRAC channel inhibitor comprises Compound II. In some embodiments, the CRAC channel inhibitor comprises Compound III. In some embodiments, ameliorating the symptoms of pancreatitis further comprises administering an analgesic drug such as an opiate. Morphine is a typical analgesic in some embodiments.

[0086] In some embodiments, the intracellular calcium signaling inhibitor has an in vitro IC determined for the compound. 50 In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration equal to, similar to, or higher than the in vitro IC value determined for the compound. 50 Values ​​of 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, 5 to achieve a tissue level concentration that is 7x, 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 from 1x to 100x.

[0087] In some embodiments, the calcium signaling inhibitor has an in vitro IC determined for the compound. 50 Delivered to achieve tissue level concentrations ranging from 1x to 100x, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x, 7x to 43x, 8x to 43x, 9x to 41x, or 10x to 40x of the value, or any non-integer number within said ranges.

[0088] In some embodiments, the calcium signaling inhibitor is at least 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, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM, 40 μM, 41 μM, 42 μM, μM, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM M, 40μM, 41μM, 42μM, 43μM, 44μM, 45μM, 46μM, 47μM, 48μM, 49μM, 50μM, 51μM, 52μM, 53μM, 54μM, 55μM, 56μM, 57μM, 58μM, 59μM, 60μM, 61μM, 62μM, 63μM, 64μM, 65μM, 66μM, 67μM, 6 8μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, 82 95 μM, 96 μM, 97 μM, 98 μM, 99 μM, 100 μM, or any non-integer multiple ranging from about 1 μM to about 100 μM, delivered to achieve tissue level concentrations.

[0089] In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration ranging from 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 said ranges.

[0090] In some embodiments, the calcium signaling inhibitor is delivered to achieve a tissue level concentration ranging from 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 said ranges.

[0091] In some embodiments, the method comprises prophylactically ameliorating a symptom of acute pancreatitis. In some embodiments, the method comprises prophylactically ameliorating a symptom of chronic pancreatitis.

[0092] Prophylactic amelioration of symptoms of pancreatitis can include reducing the severity, likelihood of occurrence, or duration of at least one symptom of pancreatitis. Prophylactic amelioration of symptoms of pancreatitis can include reducing the severity, likelihood of occurrence, or duration of at least one symptom of pancreatitis to the point where at least one symptom of pancreatitis no longer occurs in a human. In some embodiments, prophylactic amelioration of symptoms of pancreatitis includes reducing the severity, likelihood of occurrence, or duration of 2, 3, 4, 5, 6, 7, 8, 9, or more symptoms of pancreatitis, and includes reducing the severity, likelihood of occurrence, or duration of all symptoms of pancreatitis in a human, such as the symptoms of pancreatitis disclosed herein. In some embodiments, the subject is a non-human mammal, rather than a human.

[0093] In some embodiments, a person is diagnosed with gallstones. In some embodiments, the person exhibits symptoms of gallstones, such as pain, e.g., severe pain in the upper right side of the abdomen, and / or nausea and vomiting, which may steadily increase over a period of about 30 minutes to several hours. The patient may also experience referred pain between the shoulder blades or below the right shoulder.

[0094] In some embodiments, the human suffers from alcoholism. In some embodiments, the human suffers from chronic alcohol use. In some embodiments, the human suffers from at least one instance of acute alcohol intoxication.

[0095] In some embodiments, the human is exposed to a drug regimen that includes administration of at least one of steroids, such as corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogen, statins, such as cholesterol-lowering statins, antihyperglycemic agents, metformin, glypins, such as vildaglypin and sitaglypin, atypical antipsychotics, clozapine, risperidone, and olanzapine.

[0096] In some embodiments, the human is identified as having an inherited form of pancreatitis. In some embodiments, the human has a mutant allele of Trypsin1 associated with inherited pancreatitis. In some embodiments, the human has a mutant trypsinogenase associated with pancreatitis. In some embodiments, the human has a mutant allele of SPINK1 associated with inherited pancreatitis. In some embodiments, the human has a mutant allele of cystic fibrosis transmembrane conductance regulator associated with inherited pancreatitis.

[0097] In some embodiments, the human is afflicted with at least one of hypercalcemia, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreas divisum, congenital malformations of the pancreas, type 2 diabetes, pancreatic cancer, intraductal stones, vasculitis, inflammation of the microvasculature in the pancreas, Coxsackievirus infection, and Porphyra, such as acute intermittent porphyria and erythropoietic protoporphyria.

[0098] In some embodiments, the human physical condition is affected by at least one of gallstones, ethanol poisoning, alcoholism, trauma, mumps, an autoimmune disorder, a scorpion sting, hyperlipidemia, hypothermia, hyperparathyroidism, and endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid.

[0099] In some embodiments, the human physical condition is affected by at least one of Coxsackievirus, cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella zoster virus, Legionella bacteria, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungus, Ascaris parasite, Cryptosporidium cells, and Toxoplasma cells.

[0100] <Concomitant use with drugs related to pancreatitis> Disclosed herein are compositions and dosing regimens for the combined administration of a calcium channel inhibitor and a drug associated with pancreatitis. In some embodiments, the dosing regimen comprises administering to an individual a drug associated with a negative impact on pancreatic activity and an intracellular calcium signaling inhibitor.

[0101] In some embodiments, the drug associated with a negative effect on pancreatic activity is a drug selected from the list consisting of: steroids such as corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogen, statins such as cholesterol-lowering statins, antihyperglycemic agents, metformin, glypins such as vildaglypin and sitaglypin, atypical antipsychotics, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid.

[0102] In some embodiments, the intracellular calcium signaling inhibitor is an SOC inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC inhibitor. Exemplary CRAC inhibitors include Compound I. Exemplary CRAC inhibitors include GSK-7975A. Exemplary CRAC inhibitors include Compound II. Exemplary CRAC inhibitors include Compound III.

[0103] In some embodiments, the dosing regimen includes administering a calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, in conjunction with a drug associated with a negative impact on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered on the same day as the drug associated with a negative impact on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered in the same week as the drug associated with a negative impact on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered simultaneously with the drug associated with a negative impact on pancreatic activity. In some embodiments, a calcium channel inhibitor such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered in a dosing regimen pattern that is independent of the dosing pattern for drugs associated with negative effects on pancreatic activity. In some embodiments, a calcium channel inhibitor such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered via the same delivery route, such as oral or intravenous, as drugs associated with negative effects on pancreatic activity. In some embodiments, a calcium channel inhibitor such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered via a separate administration route from drugs associated with negative effects on pancreatic activity.In some embodiments, a calcium channel inhibitor such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered to a human receiving a drug associated with a negative impact on pancreatic activity only shortly after the human has shown at least one sign of an effect of the drug associated with a negative impact on pancreatic activity, e.g., via an increase in blood amylase activity or the onset of at least one symptom of pancreatitis disclosed herein. In some embodiments, a calcium channel inhibitor such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered to a human receiving a drug associated with a negative impact on pancreatic activity in a human receiving at least one sign of an effect of the drug associated with a negative impact on pancreatic activity, e.g., via an increase in blood amylase activity or the onset of at least one symptom of pancreatitis disclosed herein, or in the absence of any evidence from the human.

[0104] In some embodiments, a calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered in a composition that includes the administration of a drug associated with a negative impact on pancreatic activity. Accordingly, some embodiments disclosed herein relate to a composition comprising an intracellular calcium signaling inhibitor and at least one drug associated with a negative impact on pancreatic activity. In some embodiments, the at least one drug is selected from the list consisting of steroids, such as corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogen, statins, such as cholesterol-lowering statins, antihyperglycemic agents, metformin, glypins, such as vildaglypin and sitaglypin, atypical antipsychotics, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid.

[0105] In some embodiments, the intracellular calcium signaling inhibitor of the composition is an SOC inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC inhibitor. In some embodiments, the CRAC inhibitor comprises Compound I. In some embodiments, the CRAC inhibitor comprises GSK-7975A. In some embodiments, the CRAC inhibitor comprises Compound II. In some embodiments, the CRAC inhibitor comprises Compound III.

[0106] In some embodiments, the intracellular calcium signaling inhibitor has an in vitro IC determined for the compound. 50 In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to, near, or exceeds the in vitro IC value determined for the compound. 50 Values ​​of 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, 29 x, 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, 5 Delivered to achieve tissue level concentrations that are 7x, 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 non-integer multiples ranging from 1x to 100x.

[0107] In some embodiments, the intracellular calcium signaling inhibitor has an in vitro IC determined for the compound. 50to achieve tissue level concentrations in the range of 1x to 100x, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x, 7x to 43x, 8x to 43x, 9x to 41x, or 10x to 40x of the value, or a non-integer value within the aforementioned ranges.

[0108] In some embodiments, the intracellular calcium signaling inhibitor is 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, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM, 40 μM, 41 μM, 42 μM, 5μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 36μM, 37μM, 38μM, 39 μM, 40 μM, 41 μM, 42 μM, 43 μM, 44 μM, 45 μM, 46 μM, 47 μM, 48 μM, 49 μM, 50 μM, 51 μM, 52 μM, 53 μM M, 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 , 68μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, Delivered to achieve tissue level concentrations that are 82 μM, 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 non-integer multiples in the range of about 1 μM to about 100 μM.

[0109] In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration in the range 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 within the aforementioned ranges.

[0110] In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration in the range 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 within the aforementioned ranges.

[0111] In some embodiments, the composition further comprises at least one of an excipient, a solubilizer, a surfactant, a disintegrant, and a buffer. In some embodiments, the composition is a liquid or an emulsion. In some embodiments, the composition is a liquid, nanoparticles, a nanoparticle suspension, or a nanoparticle emulsion. In some embodiments, the composition is a tablet.

[0112] Calcium signaling and viral diseases Viral diseases occur when pathogenic viruses invade the body of an organism (host). Infectious virus particles, called virions, attach to and enter susceptible host cells. Calcium signaling regulates the entry, production, and transmission of viruses in host cells, thereby spreading viral diseases. For example, host cell calcium signaling triggers viral diseases by activating STIM1-mediated and Orai-mediated calcium influx, which further enables viruses to bud and multiply within host cells.

[0113] Viral diseases are diverse and are classified by structural characteristics such as genome type, virion shape, and replication site. Specific, non-limiting examples of viral diseases include hemorrhagic fever viruses. In some embodiments, the hemorrhagic fever virus is an arenavirus, filovirus, bunyavirus, flavivirus, rhabdovirus, or a combination thereof. Non-limiting examples of hemorrhagic fever viruses include Ebola virus, Marburg virus, Lassa virus, Junin virus, rotavirus, West Nile virus, Zika virus, Coxsackievirus, Hepatitis B virus, Epstein-Barr virus, Dengue virus, Rift Valley virus, etc.

[0114] Disclosed herein are compositions and methods for the prophylactic amelioration of viral diseases and their symptoms, such as by administering a calcium channel inhibitor, such as a CRAC inhibitor. In some embodiments, a method for ameliorating viral disease symptoms in a human is provided. In some embodiments, a method for ameliorating viral disease symptoms in a human is disclosed, the method comprising identifying a person in need of prophylactic amelioration of viral disease symptoms, and administering to the person an intracellular calcium signaling inhibitor in a dose sufficient to prophylactically ameliorate the symptoms.

[0115] In some embodiments, common symptoms of viral illness include fever or hemorrhagic diathesis. In further embodiments, symptoms of viral illness include facial flushing, chest flushing, petechiae, capillary leakage, bleeding, swelling, edema, hypotension, shock, or a combination thereof. In further embodiments, symptoms of viral illness include fatigue, muscle pain, headache, vomiting, diarrhea, or a combination thereof.

[0116] In some embodiments, the intracellular calcium signaling inhibitor is a SOC channel inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some embodiments, the CRAC channel inhibitor comprises Compound I. In some embodiments, the CRAC channel inhibitor comprises GSK-7975A. In some embodiments, the CRAC channel inhibitor comprises Compound II. In some embodiments, the CRAC channel inhibitor comprises Compound III. In some embodiments, ameliorating symptoms of a viral disease further comprises administering an antiviral drug or vaccine.

[0117] In some embodiments, the intracellular calcium signaling inhibitor has an in vitro IC determined for the compound. 50 In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to, near, or exceeds the in vitro IC value determined for the compound. 50Values ​​of 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, 29 x, 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, Delivered to achieve tissue level concentrations that are 57x, 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 non-integer multiples in the range of 1x to 100x.

[0118] In some embodiments, the intracellular calcium signaling inhibitor has an in vitro IC determined for the compound. 50 to achieve tissue level concentrations in the range of 1x to 100x, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x, 7x to 43x, 8x to 43x, 9x to 41x, or 10x to 40x of the value, or a non-integer value within the aforementioned ranges.

[0119] In some embodiments, the intracellular calcium signaling inhibitor is 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, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM, 40 μM, 41 μM, 42 μM, 5μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 36μM, 37μM, 38μM, 39 μM, 40 μM, 41 μM, 42 μM, 43 μM, 44 μM, 45 μM, 46 μM, 47 μM, 48 μM, 49 μM, 50 μM, 51 μM, 52 μM, 53 μM M, 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 , 68μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, Delivered to achieve tissue level concentrations that are 82 μM, 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 non-integer multiples in the range of about 1 μM to about 100 μM.

[0120] In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration in the range 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 within the aforementioned ranges.

[0121] In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration in the range 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 within the aforementioned ranges.

[0122] In some embodiments, the method comprises prophylactically ameliorating symptoms of an acute viral disease. In some embodiments, the method comprises prophylactically ameliorating symptoms of a chronic viral disease.

[0123] Prophylactically ameliorating a symptom of a viral disease includes reducing the severity, likelihood of onset, or duration of at least one symptom of the viral disease. Prophylactically ameliorating a symptom of a viral disease includes reducing the severity, likelihood of onset, or duration of at least one symptom of the viral disease to the point where the at least one symptom does not occur in a person. In some embodiments, prophylactically ameliorating a symptom of a viral disease includes reducing the severity, likelihood of onset, or duration of 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 symptoms of the viral disease, including reducing the severity, likelihood of onset, or duration of all symptoms of the viral disease in a person, such as the symptoms of the viral disease disclosed herein. In some embodiments, the subject is a non-human mammal rather than a human.

[0124] Calcium signaling and Th17-induced diseases T helper cells (Th cells) are important for immune system function. Th cells regulate the immune system by releasing T cell cytokines, including chemokines, interferons, interleukins, lymphokines, tumor necrosis factors, or combinations thereof. T helper 17 cells (Th17) are a subset of pro-inflammatory Th cells and are defined by their production of interleukin-17 (IL-17). Dysregulation of Th17 is associated with inflammatory and autoimmune diseases. Calcium signaling plays a critical role in regulating Th17 differentiation.

[0125] Disclosed herein are compositions and methods for the prophylactic improvement of Th17-induced diseases and their symptoms, such as by administering calcium channel inhibitors, such as CRAC inhibitors. In some embodiments, methods for improving symptoms of Th17-induced diseases in humans are disclosed. In some embodiments, methods for improving symptoms of Th17-induced diseases in humans are disclosed, the methods comprising: identifying a person in need of prophylactic improvement of symptoms of Th17-induced diseases; and administering an intracellular calcium signaling inhibitor to the person in a dose sufficient to prophylactically improve the symptoms.

[0126] In some embodiments, the symptoms of Th17-induced disease include acute inflammation. Symptoms of inflammation in humans include local redness, swelling, heat, pain, stiffness, fever, chills, fatigue, headache, loss of appetite, or a combination thereof. In some aspects, the symptoms occur on the human body, including the trunk, arms, hands, fingers, legs, feet, toes, head, neck, bones, joints, throat, nasal passages, eyes, or a combination thereof.

[0127] In other embodiments, the Th17-induced disease comprises chronic inflammation or a chronic inflammatory disease, including, by way of non-limiting example, hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, or cancer.

[0128] In a further embodiment, Th17-induced disease comprises autoimmune disease.Autoimmune disease is a disease that the body's immune system attacks normal cells.Autoimmune disease occurs in the heart, kidney, liver, lung, skin, endocrine gland, exocrine gland, digestive system, tissue, blood, nervous system or vascular system.Non-limiting examples of autoimmune disease include rheumatoid arthritis, lupus, celiac disease, psoriasis, Sjogren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, temporal arteritis, etc.

[0129] In some embodiments, the intracellular calcium signaling inhibitor is a SOC channel inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some embodiments, the CRAC channel inhibitor comprises Compound I. In some embodiments, the CRAC channel inhibitor comprises GSK-7975A. In some embodiments, the CRAC channel inhibitor comprises Compound II. In some embodiments, the CRAC channel inhibitor comprises Compound III. In some embodiments, ameliorating symptoms of Th17-induced disease further comprises administering an anti-inflammatory drug.

[0130] In some embodiments, the intracellular calcium signaling inhibitor has an in vitro IC determined for the compound. 50 In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to, near, or exceeds the in vitro IC value determined for the compound. 50 Values ​​of 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, 29 x, 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, Delivered to achieve tissue level concentrations that are 57x, 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 non-integer multiples in the range of 1x to 100x.

[0131] In some embodiments, the intracellular calcium signaling inhibitor has an in vitro IC determined for the compound. 50 to achieve tissue level concentrations in the range of 1x to 100x, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x, 7x to 43x, 8x to 43x, 9x to 41x, or 10x to 40x of the value, or a non-integer value within the aforementioned ranges.

[0132] In some embodiments, the intracellular calcium signaling inhibitor is 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, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM, 40 μM, 41 μM, 42 μM, 5μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 36μM, 37μM, 38μM, 39 μM, 40 μM, 41 μM, 42 μM, 43 μM, 44 μM, 45 μM, 46 μM, 47 μM, 48 μM, 49 μM, 50 μM, 51 μM, 52 μM, 53 μM M, 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 , 68μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, Delivered to achieve tissue level concentrations that are 82 μM, 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 non-integer multiples in the range of about 1 μM to about 100 μM.

[0133] In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration in the range 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 within the aforementioned ranges.

[0134] In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration in the range 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 within the aforementioned ranges.

[0135] In some embodiments, the method comprises prophylactically ameliorating a symptom of an acute Th17-induced disease. In some embodiments, the method comprises prophylactically ameliorating a symptom of a chronic Th17-induced disease.

[0136] Prophylactically ameliorating a symptom of a Th17-induced disease includes reducing the severity, likelihood of onset, or duration of at least one symptom of a Th17-induced disease. Prophylactically ameliorating a symptom of a Th17-induced disease includes reducing the severity, likelihood of onset, or duration of at least one symptom of a Th17-induced disease to the point where the at least one symptom does not occur in a person. In some embodiments, prophylactically ameliorating a symptom of a Th17-induced disease includes reducing the severity, likelihood of onset, or duration of 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 symptoms of a Th17-induced disease, including reducing the severity, likelihood of onset, or duration of all symptoms of a Th17-induced disease in a person, such as the symptoms of a Th17-induced disease disclosed herein. In some embodiments, the subject is a non-human mammal rather than a human.

[0137] <specific term> Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood to which the claimed subject matter belongs. In the event of multiple definitions for terms herein, those in this section prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. When a URL or other such identifier or address is mentioned, it is understood that such identifiers may change and particular information on the Internet may come and go, but that equivalent information may be found by an Internet search. Reference to such evidences the availability and public dissemination of such information.

[0138] It is understood that the foregoing general description and the following detailed description are exemplary and illustrative only and are not restrictive of the claimed subject matter. In this application, the use of the singular includes the plural unless expressly stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including" is not limiting, as are other forms such as "include," "includes," and "included."

[0139] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0140] Definitions of standard chemical terms may be found in references, including, but not limited to, Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology may be employed.

[0141] Unless specific definitions are provided, the nomenclature, laboratory methods, techniques, analytical chemistry, synthetic organic chemistry, medicinal chemistry, and pharmaceutical chemistry utilized in connection therewith described herein are art-recognized. Standard techniques may be used for chemical synthesis, chemical analysis, drug preparation, formulation, delivery, and patient treatment. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reaction and purification techniques may be performed, for example, using kits according to manufacturer's specifications, or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may generally be performed in a conventional manner and as described in the various general and more specific references cited and discussed throughout the specification.

[0142] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein, as such 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.

[0143] The terms "kit" and "article of manufacture" are used synonymously.

[0144] The term "subject" or "patient" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, members of the following mammalian classes: humans, non-human primates such as chimpanzees, and other apes and monkeys; livestock 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.

[0145] The terms "treat," "treating," and "treatment," as used herein, include prophylactically and / or therapeutically alleviating, reducing, or ameliorating the symptoms of a disease or condition; preventing further symptoms; ameliorating or preventing the underlying cause of a symptom; inhibiting a disease or condition, e.g., arresting the progression of a disease or condition; relieving a disease or condition; reversing a disease or condition; alleviating a condition caused by a disease or condition; or halting a disease or condition. As used herein, the term "target protein" refers to a protein or portion of a protein that can be bound to or interacted with by a compound described herein, such as a compound having a structure from the Compound A group. In certain embodiments, the target protein is a STIM protein. In certain embodiments, the target protein is an Orai protein.

[0146] As used herein, "STIM protein" includes, but is not limited to, mammalian STIM-1, such as human and rodent (e.g., mouse) STIM-1, D-STIM in Drosophila melanogaster, C. elegans C-STIM, and Anopheles gambiae STIM, and mammalian STIM-2, such as human and rodent (e.g., mouse) STIM-2. (See paragraphs

[0211] to

[0270] and Table 3 of US 2007 / 0031814, which are incorporated herein by reference.) As described herein, such proteins have been identified as being involved in, participating in, and / or providing for store-operated calcium entry or its regulation, cytosolic calcium buffering, and / or regulation of calcium levels in intracellular calcium stores (e.g., the endoplasmic reticulum) or calcium movement into, into, or out of intracellular calcium stores.

[0147] As used herein, "Orai protein" includes Orai1 (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 Orai1 nucleic acid sequence corresponds to GenBank accession number NM_032790, the Orai2 nucleic acid sequence corresponds to GenBank accession number BC069270, and the Orai3 nucleic acid sequence corresponds to GenBank accession number 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 related to, involved in, and / or providing for store-operated calcium entry or its regulation, cytosolic calcium buffering, and / or regulation of calcium levels in intracellular calcium stores (e.g., the endoplasmic reticulum) or calcium movement into, into, or out of intracellular calcium stores.

[0148] The term "fragment" or "derivative" when referring to a protein (e.g., STIM, Orai) means a protein or polypeptide that essentially preserves the same biological function or activity as the native protein in at least one assay. For example, a fragment or derivative of the referenced protein maintains at least about 50%, at least 75%, or at least about 95% of the activity of the native protein, as determined, for example, by a calcium influx assay.

[0149] As used herein, "amelioration" of symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to a decrease in severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or momentary, resulting from or associated with the administration of the compound or composition.

[0150] The term "modulate," as used herein, means to interact with a target protein, either directly or indirectly, so as to alter the activity of the target protein, including, by way of example only, inhibiting the activity of the target or limiting or reducing the activity of the target.

[0151] As used herein, the term "modulator" refers to a compound that changes the activity of a target. For example, a modulator can cause an increase or decrease in the magnitude of a specific 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.

[0152] As used herein, "modulation" with respect to intracellular calcium refers to the alteration or regulation of intracellular calcium, including, but not limited to, altering calcium concentrations in the cytoplasm and / or intracellular calcium storage organelles, e.g., the endoplasmic reticulum, and altering the kinetics of calcium flux into, out of, and within the cell. In embodiments, modulation refers to a decrease.

[0153] As used herein, the term "target activity" refers to a biological activity that can be modulated by a modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or disorder.

[0154] As used herein, the terms "inhibits," "inhibiting," or "inhibitor" of SOC or CRAC channel activity refer to the inhibition of store-operated or calcium release-activated calcium channel activity.

[0155] As used herein, the term "acceptable" in reference to a formulation, composition, or ingredient means having no lasting adverse effects on the health status of the subject being treated.

[0156] As used herein, the term "pharmaceutically acceptable" refers to a substance such as a carrier, diluent, or formulation that does not abrogate the biological activity or properties of the compound and that is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious way with any of the components of the composition in which it is contained.

[0157] The term "pharmaceutical composition" as used herein refers to a product resulting from the mixing or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.The term "fixed combination" means that one active ingredient, such as a compound having a structure from the group of Compound A, and an auxiliary agent are administered to a patient simultaneously, together, or sequentially as separate entities without any specific intervening time limit, where such administration provides the patient's body with effective levels of the two compounds.The latter also applies to cocktail therapy, such as the administration of three or more active ingredients.

[0158] The term "pharmaceutical composition" refers to a mixture of a compound having a structure from the Compound A group described herein with other chemical components such as carriers, stabilizers, excipients, surfactants, dispersing agents, suspending agents, thickening agents, and / or additives. Pharmaceutical compositions facilitate administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, subcutaneous, intramuscular, pulmonary, and topical administration.

[0159] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient quantity of an agent or compound being administered to relieve to some extent one or more of the symptoms of the disease or disorder being treated. As a result, the signs, symptoms, or causes of the disease may be reduced and / or alleviated, or other desired alterations to a biological system may occur. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound having a structure from the Compound A group required to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount in a particular case may be determined using techniques such as a dose escalation study.

[0160] The terms "enhance" or "enhancing," as used herein, means to increase or prolong, either in potency or duration, a desired result. 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 sufficient to enhance the effect of another therapeutic agent in a desired system.

[0161] As used herein, the term "co-administration" and the like is intended to encompass the administration of selected therapeutic agents to one patient and is 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.

[0162] As used herein, the term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

[0163] The term "diluent" refers to a chemical compound used to dilute the compound of interest before delivery. Diluents can also be used to stabilize the compound, as they can provide a more stable environment. Salts dissolved in buffers (which can also provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to, phosphate buffered saline solutions.

[0164] A "metabolite" of a compound disclosed herein is a derivative of that compound formed during metabolism of the compound. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the entire process by which a particular substance is transformed by an organism, including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes can cause specific structural changes to a compound. 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 regarding metabolism can be found in The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds in vitro with hepatocytes and analyzing the resulting compounds.

[0165] "Bioavailability" refers to the percentage of the weight of a 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 degree to which a compound disclosed herein is absorbed into the systemic circulation when the pharmaceutical composition is taken orally, compared to intravenous injection.

[0166] "Plasma concentration" refers to the concentration of a compound having a structure from the Compound A group in the plasma component of a subject's blood. It is understood that due to variability in metabolism and / or possible interactions with other therapeutic agents, the plasma concentration of the compounds described herein may vary significantly between subjects. In accordance with one embodiment disclosed herein, the plasma concentration of the compounds disclosed herein may vary between subjects. Similarly, values ​​such as the maximum plasma concentration (Cmax) or the time to reach maximum plasma concentration (Tmax), or the total area under the plasma concentration-time curve (AUC(0-∞)), may vary from subject to subject. Due to this variability, the amount necessary to constitute a "therapeutically effective amount" of a compound may vary from subject to subject.

[0167] As used herein, "calcium homeostasis" refers to the maintenance of the overall balance of intracellular calcium levels and movement, including calcium signaling, within a cell. As used herein, "intracellular calcium" refers to calcium located in a cell without specification of a specific cellular location. In contrast, "cytosolic" or "cytoplasmic" in reference to calcium refers to calcium located in the cytoplasm of a cell.

[0168] As used herein, an effect on intracellular calcium is a change in aspects 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 properties such as, for example, the kinetics, sensitivity, velocity, amplitude, and electrophysiological characteristics of calcium flux or movement occurring in a cell or portion thereof. An effect on intracellular calcium can be a change in the process of intracellular calcium regulation, including store-operated calcium entry, cytosolic calcium buffering, and calcium levels in intracellular calcium stores or the movement of calcium into, out of, or within intracellular calcium stores. Any of these aspects can be assessed in a variety of ways, including, but not limited to, assessment of calcium or other ion (especially cation) levels, calcium or other ion (especially cation) movement, fluctuations in calcium or other ion (especially cation) levels, calcium or other ion (especially cation) flux kinetics, and / or calcium or other ion (especially cation) transport across membranes. The change can be such a statistically significant change. Thus, for example, if intracellular calcium in test and control cells is said to be different, such difference may be statistically significant.

[0169] As used herein, "involved in," with reference to the association between a protein and intracellular calcium or an aspect of intracellular calcium regulation, means that when the expression or activity of the protein in a cell is reduced, altered, or eliminated, one or more aspects of intracellular calcium or intracellular calcium regulation are simultaneously or associatedly reduced, altered, or eliminated. Such alteration or reduction in expression or activity can occur by altering the expression of the gene encoding the protein by altering the level of the protein. For example, a protein related to an aspect of intracellular calcium, such as store-operated calcium entry, can therefore be a protein that provides or is involved in intracellular calcium or an aspect of intracellular calcium regulation. For example, a protein that provides store-operated calcium entry can be a STIM protein and / or an Orai protein.

[0170] 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.

[0171] As used herein, "basal" or "resting" in reference to cytosolic calcium levels refers to the concentration of calcium in the cytoplasm of a cell, e.g., an unstimulated cell, that is not exposed to a condition that results in calcium mobilization into, out of, or within the cell. Basal or resting cytosolic calcium levels can be the concentration of free calcium (i.e., calcium not bound to a cellular calcium-binding substance) in the cytoplasm of a cell, e.g., an unstimulated cell, that is not exposed to a condition that results in calcium mobilization into, out of, or within the cell.

[0172] As used herein, "translocation," with respect to ions, including cations such as calcium, refers to the movement or rearrangement (e.g., flow, etc.) of ions into, out of, or within a cell. Thus, ion movement can occur, for example, from the extracellular medium into the cell, from within the cell to the extracellular medium, from an organelle or storage site to the cytosol, from the cytosol to an organelle or storage site, from one organelle or storage site to another, from the extracellular medium to an organelle or storage site, It can be the movement of ions from intracellular organelles or storage sites to the extracellular medium, and from one location to another within the cytoplasm of a cell.

[0173] As used herein, "cation entry" or "calcium influx" into a cell refers to the entry of cations, such as calcium, into an intracellular location, such as the cytoplasm of a cell, or into the lumen of an organelle or storage site. Thus, cation entry can be, for example, the movement of cations from the extracellular medium or from an organelle or storage site into the cytoplasm of a cell, or the movement of cations from the cytoplasm or extracellular medium into an organelle or storage site. The movement of calcium from an organelle or storage site into the cytoplasm is also referred to as "calcium release" from the organelle or storage site.

[0174] As used herein, "proteins that regulate intracellular calcium" refer to cellular proteins involved in the regulation, control, and / or alteration of intracellular calcium. For example, such proteins may be involved in altering or regulating intracellular calcium in various ways, including, but not limited to, maintaining resting or basal cytoplasmic calcium levels, or participating in cellular responses to signals transmitted within the cell via mechanisms involving deviation of intracellular calcium from the 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 cell 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 regulate ion transport proteins.

[0175] As used herein, the term "ameliorate" means to diminish, prevent, alleviate, and / or reduce the effects of a disease, condition, or condition, resulting in an improvement of the disease or condition or at least partial alleviation of symptoms associated with the disease or condition, including a complete reduction such that said effects are zero or effectively zero.

[0176] As used herein, "cellular response" refers to a cellular reaction resulting from ion movement into, out of, or within a cell. A cellular response can be related, at least in part, to cellular activity that is dependent on ions such as calcium. Such activity can include, for example, cell activation, gene expression, endocytosis, exocytosis, cell trafficking, and apoptotic cell death.

[0177] 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, white blood cells, antigen-presenting cells, and natural killer cells.

[0178] As used herein, "cytokine" refers to a small soluble protein secreted by a cell that can alter the behavior or properties of the secreting cell or another cell. Cytokines bind to cytokine receptors and cause an intracellular behavior or property, such as cell proliferation, death, or 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 (B70, also known as CD86), TNF family members (TNF-α, TNF-β, LT-β, ​​CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail), and MIF.

[0179] "Store-operated calcium entry" or "SOCE" refers to a mechanism by which the release of calcium ions from intracellular stores is regulated by ion influx across the cell membrane.

[0180] A "selective inhibitor of SOC channel activity" means that the inhibitor is selective for SOC channels and does not substantially affect the activity of other types of ion channels.

[0181] By "selective inhibitor of CRAC channel activity" is meant that the inhibitor is selective for CRAC channels and does not substantially affect the activity of other types of ion channels and / or other SOC channels.

[0182] As used herein, the term "calcium" refers to the element or the divalent cation Ca 2+ It can be used to refer to.

[0183] While preferred embodiments of the present invention 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 modifications, 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 invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby. [Example]

[0184] Example 1: CRAC channel inhibition by GSK-7975A blocks necrosis in mouse and human pancreatic acinar cells Mouse pancreatic acinar cells (PACs) were extracted and incubated with a carrier (control) or the natural bile acid TLCS (taurolithocholic acid 3-sulfate) in the presence or absence of GSK-7975A. Cells were contacted with propidium iodide and analyzed for cell necrosis. TLCS treatment of individual cells in vitro mimics the effects of gallstones or other blockages during pancreatic secretion in vivo.

[0185] As shown in Figure 1A, TLCS induced necrosis in approximately 45% of cells during the experimental period. Addition of 10 μM GSK-7975A reduced this percent necrosis in half to approximately 23%. Asterisks indicate statistically significant changes. Cells not treated with TLCS demonstrated approximately 10% necrosis. These results demonstrate that GSK-7975A reduces the necroptosis-inducing effect of TLCS on mouse PACs.

[0186] Human pancreatic acid complexes (PACs) were extracted and incubated with carrier (control) or the natural bile acid TLCS in the presence or absence of GSK-7975A. Cells were exposed to propidium iodide and analyzed for cell necrosis. TLCS treatment of individual cells in vitro mimics the effects of gallstones or other obstructions during pancreatic secretion in vivo.

[0187] As shown in Figure 1B, TLCS induced necrosis in approximately 45% of cells during the experimental period. Addition of 10 μM GSK-7975A reduced this percent necrosis to approximately 30%. Asterisks indicate statistically significant changes. Cells not treated with TLCS demonstrated approximately 23% necrosis. This result demonstrates that GSK-7975A reduces the necroptosis-inducing effect of TLCS on human PACs.

[0188] Example 2: A CRAC channel inhibitor (GSK-7975A) blocks histopathological changes in a mouse model of AP A mouse model of acute pancreatitis was used to evaluate the effects of CRAC inhibitors on pancreatic histopathological progression. Caerulein was used to overstimulate CCK receptors in the canonical calcium signaling pathway in the mouse pancreas. TLCS was used to induce acute pancreatitis by simulating excess bile acids, as experienced in gallstone-induced acute pancreatitis. Fatty acid ethyl esters (FAEEs) were used to simulate alcohol-induced acute pancreatitis. Mice were treated with acute pancreatitis reagents (caerulein (Figure 2A), TLCS (Figure 2B), or FAEE (Figure 2C)) alone or with IC of CRAC inhibitors. 50 The patients were treated with the CRAC inhibitor GSK-7975A at 10x or 40x the dose.

[0189] It has been observed that GSK-7975A significantly reduces the total histopathological score in treated mice compared to mice treated with the agent in the absence of a CRAC inhibitor. This effect is statistically significant and is 10x IC 50 More than 40xIC 50The in vitro IC was substantially more pronounced at 100 mg / kg / day, but was observed at lower concentrations. Asterisks indicate statistically significant changes. 50 GSK-7975A at doses achieving tissue levels greater than 10 or 40 times the normal values ​​results in a significant reduction in pancreatic histopathology.

[0190] The results shown in Figures 2A, 2B, and 2C demonstrate that CRAC inhibitors can ameliorate the histopathological manifestations of acute pancreatitis, an effect observed regardless of the inducing agent or the type of acute pancreatitis being modeled.

[0191] Example 3: Compound I and GSK-7975A inhibit CRAC channels Compound I and GSK-7975A were analyzed for their inhibitory effects on CRAC channels. Channels containing Orai1 / STIM1 and Orai2 / STIM1 were analyzed. As shown in Figure 3A, Compound I inhibited CRAC channels with an average IC of 119 nM. 50 Orai1 / STIM1 channels at 1000 kJ / s, and an average IC of 895 nM 50 As shown in Figure 3B, GSK-7975A inhibited Orai2 / STIM1 channels with an average IC of 398 nM. 50 Orai1 / STIM1 channels at 1000 kJ / s, and an average IC of 1453 nM 50 It was determined that Compound I inhibited Orai2 / STIM1 channels at 1000 kJ / min. Compound I is approximately 4-fold more potent against Orai1-type CRAC channels than GSK-7975A. Both compounds are more potent against Orai1 than Orai2-type CRAC channels.

[0192] These results indicate that the effects observed for GSK-7975A on calcium signaling can be generalized to CRAC inhibitors and that CRAC inhibitors other than GSK-7975A may be superior to GSK-7975A on some parameters.

[0193] Example 4: Compound I inhibits store-operated Ca2+ agonism in mouse pancreatic acinar cells 2+ Blocking inflow (SOCE) Mouse PACs were isolated and analyzed for the effect of CRAC inhibitors on calcium reuptake into the ER. Cells were treated with cyclopiazonic acid (CPA) alone (Figure 4A) or in combination with the CRAC inhibitor Compound I (Figure 4B) to activate CRAC channels and re-uptake Ca 2+ After 15 minutes of calcium release, cells were provided with excess calcium and monitored for calcium uptake into the ER. It is observed that cells treated with an inhibitor of CRAC do not demonstrate calcium reuptake.

[0194] This result indicates that CRAC inhibitors can block the cell's ability to refill the ER with calcium for subsequent rounds of signaling.

[0195] Example 5: Compound I and GSK-7975A dose-dependently block SOCE in mouse pancreatic acinar cells Mouse PACs were treated with the CRAC inhibitor Compound I (FIG. 5A) or GSK-7975A (FIG. 5B) and monitored for their rate of calcium uptake. Both CRAC inhibitors reduced the rate of store-operated calcium entry into the ER to 50% of control levels after treatment with 700 nM of inhibitor. Compound I blocks 100% of reuptake at 10 mM.

[0196] This example demonstrates that multiple CRAC inhibitors each act to inhibit SOCE in mammalian PAC.

[0197] Example 6: Compound I inhibits CCK-induced Ca2+ receptor agonism in mouse pancreatic acinar cells 2+ Block the inflow. Mouse PACs were monitored for their calcium uptake after treatment with 10 nM CCK. Cells were treated with CCK, then provided with 1.8 mM calcium, and calcium reuptake was monitored. It was observed that cells pre-treated with CRAC inhibitors (FIG. 6B) demonstrated substantially reduced calcium reuptake compared to untreated cells (FIG. 6A). Pre-treatment with Compound I reduced calcium reuptake to nearly 0% of control. GSK-7975A reduced calcium reuptake to approximately 30% of control.

[0198] These results indicate that CRAC inhibitors may be effective in reducing hyperactive calcium signaling in PAC.

[0199] Example 7: Compound I inhibits multiple cytokines Compound I was tested for its inhibitory effects on a number of cytokines. The cytokines INF-gamma, IL-4, and IL-4 receptor are expressed on acinar cells; the cytokines IL-1 beta, IL-6, IL-10, and TNF-alpha are expressed in acinar cells; and IL-2 and IL-7, cytokines important in T cell function, were tested for their inhibitory effects on the CRAC inhibitor Compound I. T cells in bulk human PBMCs were stimulated with plate-bound anti-CD3 / anti-CD28 in buffer plus 10% serum for 48 hours. Released cytokines were measured by Millipore Luminex. The results are shown in Figure 7. In human PBMCs, Compound I potently inhibits the release of multiple cytokines that play important roles in T cell function.

[0200] These cytokine data, together with the PAC data, support the conclusion that Compound I has a dual effect in acute pancreatitis, inhibiting both immune cell and pancreatic acinar cell signaling pathways and death.

[0201] Example 8: Compound I shows potent efficacy in the murine calcineurin model of acute pancreatitis. Mice were prophylactically treated with a CRAC inhibitor or vehicle, and then challenged with CCK to induce acute pancreatitis.Prophylactically administered intraperitoneally (ip) Compound I significantly and dose-dependently reduced cerulein-induced pathology in the pancreas of mice (C57B6 mice).This effect was significantly lower than that of the positive control CsA at 5 mg / kg, and increased dose-dependently.See Figure 8A.This treatment demonstrated a dose-proportional increase in Compound I levels in the pancreas after intraperitoneal injection (see Figure 8B), which corresponds to the positive results in Figure 8A above.

[0202] These results indicate that administration of CRAC prior to or in conjunction with a second drug suspected of causing or increasing the risk of acute pancreatitis may prophylactically protect against or reduce the risk of acute pancreatitis.

[0203] Example 9: Compound I reduces serum amylase and serum lipase levels in the murine caerulein model of acute pancreatitis Mice were either untreated (control), treated with CCK alone (vehicle), or treated with CCK in combination with CsA or a CRAC inhibitor at the indicated doses. Serum amylase (Figure 9A) and lipase (Figure 9B) activities (IU / L) were measured.

[0204] The CRAC inhibitor Compound I acted as well as or better than the positive control CsA at the maximum concentration of 20 mg / kg. Compound I produced a significant and dose-dependent reduction in caerulein-induced serum amylase and serum lipase activity.

[0205] Example 10: Compound I reduces pancreatic pathology in a therapeutic murine caerulein model. Seven hourly intraperitoneal injections of caerulein were administered to induce pancreatitis, and the animals were sacrificed 8 hours after the first injection. Compound I was administered intraperitoneally 30 minutes before the first caerulein injection (prophylaxis) or after the third injection (treatment). CsA was administered orally (po) on the same schedule as Compound I. The results are shown in Figure 10.

[0206] Histopathological scores were determined based on the observation of acinar cell degeneration, coagulation necrosis, and inflammation, as well as edema measurements. Compound I, when administered after the third caerulein injection, significantly reduced caerulein-induced pathology in the pancreas by 35%, consistent with its therapeutic effect. Prophylactic treatment with Compound I also reduced pathology by 26%.

[0207] The results show that CRAC inhibitors such as Compound I have a substantial effect on pancreatic histopathological scores when administered prophylactically or therapeutically.

[0208] Example 11: Compound I inhibits TLCS-induced Ca2+ production in mouse pancreatic acinar cells 2+ Block the inflow. Mouse PACs were treated with 500 μM TLCS and 0.1 μM or 3 μM of the CRAC inhibitor Compound I. Cytosolic calcium levels (measured as the F345 / F380 ratio) were measured for each treatment. TLCS mobilizes Ca from intracellular stores (not shown). 2+ In this experiment, 1 μM or 3 μM of Compound I inhibited the TLCS-induced Ca release and initiated SOCE. 2+ The influx was completely blocked, and the results are shown in Figure 11.

[0209] The results indicate that CRAC inhibitors may be effective in positively affecting calcium signaling in gallstone-associated acute pancreatitis in mammals.

[0210] Example 12: Compound I and other CCIs inhibit TLCS-induced amylase release in mouse pancreatic acinar cells Amylase release from PAC has an ER calcium-dependent and a CRAC / cytosol calcium-dependent component. The calcium-dependent component is blocked by the introduction of EGTA, a divalent cation chelator. Mouse acinar cells were treated with TLCS and vehicle, EGTA, or a CRAC inhibitor, such as Compound I, GSK-7975A, or Compound II, and monitored for amylase release. It was observed that the CRAC inhibitor mimicked EGTA in its effect on amylase release. See Figure 12.

[0211] This result indicates that CRAC inhibitors block calcium reuptake into the ER after TLCS-induced calcium release, thereby mimicking the effect of EGTA on inhibiting amylase release.

[0212] Example 13: Compound I inhibits TLCS-induced necrosis in mouse pancreatic acinar cells Mouse PACs were treated with DMSO, DMSO + 500 μM TLCS, or DMSO + 500 μM TLCS + 1 μM CRAC inhibitor Compound I. Cell necrosis was measured as %PI uptake. The CRAC inhibitor Compound I inhibits TLCS-induced necrosis in mouse PACs.

[0213] These data indicate that Ca 2+ Together with the and amylase data, this demonstrates that Compound I is effective in the TLCS model of AP.

[0214] Example 14: Phase II Study of the Safety and Efficacy of Compound I, GSK-7975A, and Compound II in Patients with Acute Pancreatitis The objective of this Phase II study is to investigate the safety, tolerability, PK, PD, and efficacy of single and repeated intravenous injections of calcium signaling inhibitors, such as Compound I, GSK-7975A, and Compound II, or compounds selected from the Compound A group, in patients with acute pancreatitis and concomitant SIRS.

[0215] Patients: The study will enroll 30 patients at high risk of developing moderate or severe pancreatitis, assessed as having a SIRS score of 2 or greater at study entry.

[0216] standard: Inclusion criteria: All subjects must use acceptable contraception to ensure they remain free of pregnancy during the study and for at least 12 weeks after dosing for men and 32 weeks after dosing for women. Weight range of 55-95kg plus 18.5-35kg / m 2 Body mass index in the range. · Subjects must be able to give informed consent and be able to comply with study requirements and timetables; Male and female subjects aged 18 years or older are eligible. Subjects must have experienced their first episode of acute pancreatitis in their lifetime. The diagnosis of acute pancreatitis must be based on two of the following three criteria: (1) typical epigastric pain; (2) elevated serum amylase and / or lipase levels at least three times the upper limit of normal; and (3) contrast-enhanced CT scan or abdominal ultrasound demonstrating changes consistent with acute pancreatitis. Subjects must demonstrate a medical history supporting an alcoholic, hypertriglyceridemic, or biliary etiology of the current episode of pancreatitis (for biliary pancreatitis, ultrasound imaging must rule out stone obstruction at study screening). Subjects must demonstrate a BISAP score of 3 or greater. Study treatment can be initiated within 48 hours of symptom onset.

[0217] Exclusion criteria: · High likelihood of invasive intrabiliary intervention (e.g., ERCP) in the next week. · Recurrent pancreatitis. · CT evidence of pancreatic necrosis at study entry. Severe chronic renal failure (dietary modification in renal disease with a prescription of 30 mL / min or dependent on renal dialysis). · New York Heart Association heart failure class II or higher. · Oxygen-dependent chronic obstructive pulmonary disease (COPD). Liver cirrhosis. · Severe anemia (hemoglobin less than 8g / dL). Hematocrit less than 35% or greater than 45% at study entry (fluids may be administered to correct hematocrit prior to randomization as long as study treatment begins within 48 hours of symptom onset). · Serum alanine aminotransferase greater than 250 IU / L at study entry. · Clinical suspicion of ascending cholangitis at study entry. Active gastrointestinal bleeding. · Current malignancy (other than basal cell carcinoma of the skin) that is not in remission. · Altered mental status. · Current breastfeeding or pregnancy. Women of childbearing potential (who are less than 2 years postmenopausal or not surgically sterilized) who are not willing to use adequate and effective contraception. Known hypersensitivity to any component of the investigational drug. Dependent relationships with researchers or sponsors. Participation in a trial of an investigational drug during this clinical trial or within 30 days prior to the start of this clinical trial.

[0218] Study Design: The study is a randomized, double-blind, placebo-controlled, multicenter, multinational, parallel-arm study comparing a placebo group with a CRAC inhibitor group treated intravenously with a CRAC inhibitor twice daily for 7 consecutive days.

[0219] The study will enroll 45 patients at high risk of developing moderate or severe pancreatitis, assessed as having a SIRS score of 2 or greater at study entry.

[0220] The primary endpoint of the study was the effect of a CRAC inhibitor on systemic inflammation during acute pancreatitis, as reflected by changes in SIRS scores or plasma levels of C-reactive protein (CRP).

[0221] Administration of the substance in the clinical trial will begin within 24 hours of the onset of acute pancreatitis symptoms or within 18 hours of hospitalization. Subjects will be randomized 1:1 to receive either a CRAC inhibitor or placebo in one of two doses. Serum levels of the CRAC inhibitor will also be monitored at the end of each 2-hour infusion.

[0222] The duration of the study per individual subject was 14 days and consisted of a screening assessment, a part of an in-clinic observation period of at least 7 days, followed by a double-blind treatment period of up to 7 days, and a final follow-up visit on day 14.

[0223] Primary endpoint: · Serum levels of C-reactive protein. Changes in SIRS over 48 hours. · Blood amylase and lipase levels.

[0224] Secondary endpoints, CRAC inhibitor vs. placebo: · Safety of CRAC inhibitors in this patient population according to routine safety laboratory testing. · Physical examination and monitoring of vital signs, ECG and adverse event reporting. · The effect of CRAC inhibitors on other plasma inflammatory markers (e.g., interleukin-6, matrix metalloproteinase 9, tumor necrosis factor alpha). The effect of CRAC inhibitors on the clinical course of pancreatitis (based on changes in clinical rating scales, such as the Bedside Index for Severity of Acute Pancreatitis (BISAP), Systemic Inflammatory Response Syndrome (SIRS) and Acute and Chronic Physiological Classification Evaluation II (APACHE II) scores, and on contrast-enhanced abdominal computed tomography (CT) scans) Progression of Sequential Organ Failure Assessment (SOFA) scores Progression of Multiple Organ Dysfunction Score (MODS) Progression of systemic inflammatory response syndrome · Progression of pro- and anti-inflammatory mediators (IL-1RA, IL-10, IL-6, IL-18, TNF-α, ICAM-1, IL-10, etc.). · Increased attention to high dependency or intensive care unit and length of hospital stay.

[0225] Example 15: Compound I inhibits Junin virus budding in infected VeroE6 cells. VeroE6 cells infected with live-attenuated Candid-1 JUNV were treated with DMSO, DMSO + 500 μM TLCS, DMSO + 500 μM TLCS + 1 μM CRAC inhibitor Compound I, DMSO + 500 μM TLCS + 10 μM Compound I, DMSO + 500 μM TLCS + 25 μM Compound I, or DMSO + 500 μM TLCS + 50 μM Compound I. Infectious virions produced from these cells were quantified in a focus formation assay. Enumeration of JUNV foci revealed a statistically significant, dose-dependent reduction in JUNV virus production after treatment with Compound I.

[0226] These data indicate that Ca 2+ Together the data show that compound I is effective in inhibiting viral budding of JUNV virus.

[0227] Example 16: Compound I inhibits store-activated Ca 2+ Specifically inhibits influx-dependent Th1, Th2, and Th17 differentiation. Naive and stimulated murine T cells cultured under Th1, Th2, and Th17 polarization conditions are treated with DMSO, DMSO + 500 μM TLCS, or DMSO + 500 μM TLCS + 1 μM CRAC inhibitor Compound I. 2+Influx (SOCE) is quantified for each treatment. Compound I blocks SOCE more strongly in differentiated Th17 cells than in naive, Th1, or Th2 cells. Furthermore, in the presence of Compound I, the IL-17A production by Th17 cells is more severely affected than the IFN-γ and IL-4 production by Th1 and Th2 cells, respectively.

[0228] These data indicate that Ca 2+ and expression data for additional transcription factors (i.e., IL-17A, RORα, and RORγt), indicating that compound I is effective in inhibiting Th17 differentiation.

Claims

1. 1. Use of an intracellular calcium signaling inhibitor in the manufacture of a medicament for ameliorating symptoms of acute pancreatitis in a human, comprising: wherein the symptoms are symptoms of acute pancreatitis, and 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 or a pharmaceutically acceptable solvate thereof.

2. The use described in claim 1, wherein the symptoms are symptoms of severe acute pancreatitis.

3. The use described in claim 1, wherein the symptoms are symptoms of moderate acute pancreatitis.

4. The use described in claim 1, wherein the intracellular calcium signaling inhibitor is an SOC channel inhibitor.

5. The use described in claim 1, wherein the intracellular calcium signaling inhibitor is a CRAC channel inhibitor.

6. The use described in claim 1, wherein the intracellular calcium signaling inhibitor inhibits a channel containing the STIM1 protein.

7. The use described in claim 1, wherein the intracellular calcium signaling inhibitor inhibits a channel containing the Orai1 protein.

8. The use described in claim 1, wherein the intracellular calcium signaling inhibitor inhibits a channel containing the Orai2 protein.

9. The use of any one of claims 1-8, wherein the symptoms include at least one of pancreatic inflammation and edema, upper abdominal pain radiating to the back, left upper abdominal pain radiating to the back, nausea, vomiting, vomiting worsened by eating, high heart rate, tachycardia, high respiratory rate, hypertension, hypotension, dehydration, abdominal tenderness, fever, chills, peritonitis, hemodynamic instability, and reflex intestinal paralysis.

10. The use described in any one of claims 1 to 8, wherein the symptoms include an inflammatory response.

11. The use described in any one of claims 1 to 8, wherein the symptoms include at least one of pancreatic necrosis and damage to organs outside the pancreas.

12. The use of any one of claims 1 to 8, wherein the symptoms include at least one of persistent abdominal pain, digestive abnormalities, fat malabsorption, pain during food intake, weight loss, increased serum amylase activity, increased serum lipase activity, increased inflammatory marker of CRP, decreased bicarbonate production, increased fecal elastase levels, increased serum trypsinogen levels, pancreatic calcification, increased serum bilirubin levels, increased alkaline phosphatase levels, and hypertriglyceridemia.

13. The use described in any one of claims 1 to 8, wherein the symptoms include at least one of elevated ESR levels, elevated IgG4 levels, increased rheumatoid factor, the presence of ANA antibodies, and the presence of anti-smooth muscle antibodies.

14. The use of any one of claims 1-8, wherein the symptoms include at least one of abdominal pain, increased blood amylase levels, increased blood lipase levels, pancreatic enlargement, nausea, vomiting, internal bleeding, intestinal paralysis, fever, jaundice, weight loss, and increased heart rate.

15. The use described in any one of claims 1 to 8, wherein the symptoms include elevated blood levels of amylase.

16. The use described in any one of claims 1 to 8, wherein the symptoms include elevated blood levels of lipase.

17. The use described in any one of claims 1-8, wherein the symptoms include findings of necrosis on computed tomography (CT) scan.

18. The use described in any one of claims 1-8, wherein the symptoms include premature digestive enzyme activation.

19. The use described in claim 18, wherein the precocious digestive enzyme activation occurs in the human pancreas.

20. The use described in claim 18, wherein the enzyme includes trypsin.

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