Pancreatitis treatment

Abstract

This paper provides a method related to the improvement of pancreatitis through the pharmaceutically mediated manipulation of calcium signaling. [Solution] The method includes the steps of identifying a person who needs improvement in the symptoms of pancreatitis, and administering an intracellular calcium signaling inhibitor to the person in a dose sufficient to improve the symptoms.

Description

[Technical Field]

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

[0002] Acute pancreatitis is the leading cause of gastrointestinal hospitalizations and major cost burdens in the United States. Acute pancreatitis has a mortality rate of 10-25% in severely ill patients and 3-5% overall. No disease has yet altered the available treatment options for victims of this illness. [Overview of the project]

[0003] Embodiments relating to methods for improving symptoms of pancreatitis in mammals such as humans are provided herein. In other embodiments, methods for improving symptoms of viral infections in mammals such as humans are described herein. In further embodiments, methods for improving symptoms of T helper 17 cell (Th17)-induced inflammation and autoimmune diseases are described herein.

[0004] In some embodiments, the method includes identifying a person in need of improvement of symptoms of pancreatitis and administering an intracellular calcium signaling inhibitor to the person in a dose sufficient to improve the symptoms. In other embodiments, the method includes identifying a person in need of improvement of symptoms of a viral disease and administering an intracellular calcium signaling inhibitor to the person in a dose sufficient to improve the symptoms. In further embodiments, the method includes identifying a person in need of improvement of symptoms of a Th17-induced disease and administering an intracellular calcium signaling inhibitor to the person in a dose sufficient to improve the symptoms. 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 intracellular calcium signaling inhibitor inhibits channels containing the STIM1 protein. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the Orai1 protein. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the Orai2 protein.

[0005] In some embodiments, intracellular calcium signaling inhibitors are compounds having the following structure:

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

[0007] 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)pyrazine-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)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. In some embodiments, the intracellular calcium signaling inhibitor is the following compound (collectively referred to as "Compound A"): N-(5-(6-ethoxy-4-methylpyridine-3-yl)pyrazine-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazole-5-yl)pyridine-2-yl) -3,5-difluoroisonicotinamide, N-(4-(1-ethyl-3-(thiazole-2-yl)-1H-pyrazole-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)pyrazine-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)phenyl)-1H-pyrazole-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazole -1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazole-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazole-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide,3-Fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)-N-((3-methylisothiazole-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxyno[2,3-b]pyridine-6-yl)pyridine-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazole-2-yl)-1H-pyrazole-5-yl)pyrimidine-2-amine, 3,5 -Difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazole-2-yl)-1H-pyrazole-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)-N-(2,4,6-trifluorobenzyl)pyridine-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)pyridine-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2- Methylbenzo[d]oxazole-6-yl)pyrazine-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridine-3-yl)thiazole-2-yl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)pyridine-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl) -1H-pyrazole-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazole-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. In some embodiments, the symptoms are those of acute pancreatitis. In some embodiments, the symptoms are inflammation and edema of the pancreas, upper abdominal pain radiating to the back, upper left abdominal pain radiating to the back, nausea, vomiting, vomiting worsened by eating, high heart rate, tachycardia, high respiratory rate, hypertension,The 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, malabsorption of fats, pain during food intake, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP as an inflammatory marker, decreased bicarbonate production, elevated fecal elastase levels, elevated serum trypsinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels. In some embodiments, the symptoms include at least one assay of any of the following: elevated ESR levels, elevated IgG4 levels, increased rheumatoid factor, presence of ANA antibodies, presence of anti-smooth muscle antibodies, and symptoms that can identify chronic pancreatitis in humans. In some embodiments, the symptoms include steatorrhea, 7 grams or more of stool or fecal steatorrhea over 24 hours with a 100 g fatty diet, and at least one of fecal elastase in a stool sample at a value of less than 200 μg / g. In some embodiments, the symptoms include at least one of abdominal pain, elevated blood amylase levels, elevated 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 elevated blood amylase levels. In some embodiments, the symptoms include elevated blood lipase levels. In some embodiments, the symptoms include the discovery of necrosis by computed tomography (CT) scans. 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.

[0008] Some embodiments relate to methods for preventing or improving symptoms associated with pancreatic disorders in humans at risk of pancreatic disorders. In some embodiments, the method includes the steps of: identifying humans with risk factors associated with pancreatic disorders; and administering an intracellular calcium signaling inhibitor in a dose sufficient to prevent or improve the above-mentioned side effects. 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 intracellular calcium signaling inhibitor is a compound having a structure from the group of compounds A, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. 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)pyrazine-2-yl)-2-fluoro-6-methylbenzamide. In some embodiments, pancreatic disorders include symptoms of acute pancreatitis. In some embodiments, pancreatic disorders include symptoms of chronic pancreatitis. In some embodiments, a person suffers from pancreatitis as a result of receiving a medication regimen that includes the administration of at least one of the following: corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, steroids such as valproic acid, L-asparaginase, azathioprine, and estrogen; statins such as cholesterol-lowering statins; antihyperglycemic agents; gliptins such as metformin, vildagliptin, and sitagliptin; atypical antidepressants; clozapine, risperidone, and olanzapine. In some embodiments, a person is identified as having a genotype of pancreatitis. In some embodiments, a person has at least one mutant allele of trypsin-1 encoding trypsinogen, SPINK1 encoding a trypsin inhibitor, and a cystic fibrosis membrane conductance regulator.In some embodiments, humans suffer from pancreatitis as a result of suffering from hypercalcemia, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic duct fusion anomaly, congenital pancreatic malformation, type 2 diabetes mellitus, pancreatic cancer, pancreatic ductal stones, vasculitis, inflammation of microvessels in the pancreas, coxsackievirus infection, and at least one of porphyrias, such as acute intermittent porphyria and erythroblastic protoporphyria. In some embodiments, the physical health conditions of the above humans are affected by gallstones, ethanol poisoning, alcoholism, trauma, mumps, autoimmune disorders, scorpion stings, hyperlipidemia, hypothermia, hyperparathyroidism, and at least one of endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid. In some embodiments, the health condition of the human body described above is affected by at least one of the following: coxsackievirus, cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella, Leptospira bacteria, Mycoplasma bacteria, Salmonella, Aspergillus fungi, roundworm parasites, Cryptosporidium cells, and Toxoplasma cells.

[0009] Some embodiments relate to methods for preventing or improving symptoms associated with viral diseases in humans at risk of viral diseases. In some embodiments, the method comprises the steps of: identifying a human having risk factors associated with viral diseases; and administering an intracellular calcium signaling inhibitor in a dose sufficient to prevent or improve the above-mentioned side effects. Some embodiments relate to compositions used for improving symptoms of viral diseases in humans, comprising the steps of identifying a human requiring improvement of symptoms of a viral disease, and administering an intracellular calcium signaling inhibitor to the human in a dose sufficient to improve the above-mentioned symptoms. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the STIM1 protein. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the Orai1 protein. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the Orai2 protein. In some embodiments, the intracellular calcium signaling inhibitor is a compound having a structure from the group of compounds A, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. 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)pyrazine-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)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. In some embodiments, the intracellular calcium signaling inhibitor inhibits the budding of a viral disease. In some embodiments, the viral disease is a hemorrhagic fever virus.In further embodiments, the hemorrhagic fever virus is an arenavirus, filovirus, bunyavirus, flavivirus, rhabdovirus, or a combination thereof. In further embodiments, the hemorrhagic fever virus is an 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, the symptoms are fever or hemorrhagic diathesis. In further embodiments, the symptoms of the viral illness are at least one of facial flushing, chest flushing, petechiae, capillary leakage, bleeding, swelling, edema, hypotension, shock, malaise, muscle pain, headache, vomiting, diarrhea, or a combination thereof.

[0010] Some embodiments relate to methods for preventing or improving symptoms associated with Th17-induced disease in humans at risk of Th17-induced disease. In some embodiments, the method comprises the steps of: identifying a human having risk factors associated with Th17-induced disease; and administering an intracellular calcium signaling inhibitor in a dose sufficient to prevent or improve the above-mentioned side effects. Some embodiments relate to compositions used for improving symptoms of Th17-induced disease in humans, comprising the steps of: identifying a human requiring improvement of symptoms of pancreatitis; and administering an intracellular calcium signaling inhibitor to the human in a dose sufficient to improve the above-mentioned symptoms. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the STIM1 protein. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the Orai1 protein. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the Orai2 protein. In some embodiments, the intracellular calcium signaling inhibitor is a compound having a structure from the group of compounds A, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. 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)pyrazine-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)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. In some embodiments, the intracellular calcium signaling inhibitor inhibits the differentiation of Th17 cells. 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, Th17-induced diseases are autoimmune diseases. In further embodiments, autoimmune diseases include rheumatoid arthritis, lupus, celiac disease, psoriasis, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes mellitus, alopecia areata, vasculitis, or temporal arteritis. In some embodiments, the symptoms of a 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 torso, arms, hands, fingers, legs, feet, toes, head, neck, bones, joints, throat, sinuses, eyes, or a combination thereof.

[0011] Several embodiments relate to compositions comprising an intracellular calcium signaling inhibitor and at least one drug having a negative effect on pancreatic activity. In some embodiments, the drug is selected from the list consisting of: corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, steroids such as valproic acid, L-asparaginase, azathioprine, and estrogen, statins such as cholesterol-lowering statins, antihyperglycemic agents, gliptins such as metformin, vildagliptin, and sitagliptin, atypical antidepressants, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid. In some embodiments, the intracellular calcium signaling inhibitor is a 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 compounds A, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. 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)pyrazine-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)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug.

[0012] Several embodiments relate to a drug regimen comprising the administration of a drug associated with a negative effect on pancreatic activity to an individual and the administration of an intracellular calcium signaling inhibitor. In some embodiments, the drug is selected from the following list: corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, steroids such as valproic acid, L-asparaginase, azathioprine, and estrogen, statins such as cholesterol-lowering statins, antihyperglycemic agents, gliptins such as metformin, vildagliptin, and sitagliptin, atypical antidepressants, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid. In some embodiments, the intracellular calcium signaling inhibitor is a 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 group A, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. 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)pyrazine-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)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug.

[0013] Several embodiments relate to compositions used to improve symptoms of pancreatitis in humans, comprising the steps of identifying a human being in need of improvement of symptoms of pancreatitis and administering an intracellular calcium signaling inhibitor to the human being in a dose sufficient to improve the symptoms. 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 intracellular calcium signaling inhibitor inhibits channels containing the STIM1 protein. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the Orai1 protein. In some embodiments, the intracellular calcium signaling inhibitor inhibits channels containing the Orai2 protein. In some embodiments, the intracellular calcium signaling inhibitor is a compound having a structure from the group of compounds A, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. 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)pyrazine-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)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. 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 the symptoms of acute pancreatitis. In some embodiments, the symptoms include inflammation and edema of the pancreas, upper abdominal pain radiating to the back, upper left 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 bowel paralysis. In some cases, the symptoms are those of severe pancreatitis.In some embodiments, the symptoms include at least one of pancreatic necrosis and damage to extrapancreatic organs. In some embodiments, the symptoms are symptoms of chronic pancreatitis. In some embodiments, the symptoms include at least one of persistent abdominal pain, digestive abnormalities, malabsorption of fats, pain during food intake, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP as an inflammatory marker, decreased bicarbonate production, elevated fecal elastase levels, elevated serum trypsinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels. In some embodiments, the symptoms include at least one of any of the following assays: elevated ESR levels, elevated IgG4 levels, increased rheumatoid factor, presence of ANA antibodies, presence of anti-smooth muscle antibodies, or symptoms that can identify chronic pancreatitis in a human. In some embodiments, the symptoms include steatorrhea, 7 grams or more of stool or fecal steatorrhea over 24 hours with a 100 g fatty diet, and at least one of fecal elastase in a stool sample at a value of less than 200 μg / g. In some embodiments, the symptoms include 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, premature digestive enzyme activation occurs in the human pancreas described above. In some embodiments, the enzyme includes trypsin.

[0014] Some embodiments relate to compositions used to prevent or improve symptoms associated with pancreatic disorders in humans at risk of pancreatic disorders, and include the steps of: identifying humans with risk factors associated with pancreatic disorders; and administering an intracellular calcium signaling inhibitor in a dose sufficient to prevent or improve the above-mentioned side effects. 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 intracellular calcium signaling inhibitor is a compound having a structure from the group of compounds A, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. 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)pyrazine-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)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. In some embodiments, the pancreatic disorder includes symptoms of acute pancreatitis. In some embodiments, the pancreatic disorder includes symptoms of chronic pancreatitis. In some embodiments, a person receives a medication regimen comprising the administration of at least one of the following: corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, steroids such as valproic acid, L-asparaginase, azathioprine, and estrogen, statins such as cholesterol-lowering statins, antihyperglycemic agents, gliptins such as metformin, vildagliptin, and sitagliptin, atypical antidepressants, clozapine, risperidone, and olanzapine. In some embodiments, humans are identified as having a pancreatitis genotype. In some embodiments, humans have at least one mutant allele of trypsin-1 encoding trypsinogen, SPINK1 encoding a trypsin inhibitor, and a cystic fibrosis membrane conductance regulator.In some embodiments, humans suffer from hypercalcemia, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic duct fusion anomaly, congenital pancreatic malformations, type 2 diabetes mellitus, pancreatic cancer, intraductal gallstones, vasculitis, inflammation of microvessels in the pancreas, coxsackievirus infection, and at least one of porphyrias, such as acute intermittent porphyria and erythroblastic protoporphyria. In some embodiments, the physical health conditions of the above humans are affected by gallstones, ethanol poisoning, alcoholism, trauma, mumps, autoimmune disorders, scorpion stings, hyperlipidemia, hypothermia, hyperparathyroidism, and at least one of endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid. In some embodiments, the health condition of the human body described above is affected by at least one of the following: cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungi, roundworm parasites, Cryptosporidium cells, and Toxoplasma cells.

[0015] <Integration by reference> All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference.

[0016] In particular, PCT application publication WO2011 / 139489A2, published on November 10, 2011, is incorporated herein by reference in its entirety; PCT application publication WO2009 / 035818, published on March 19, 2009, is incorporated herein by reference in its entirety; PCT application publication WO2010 / 025295, published on June 17, 2010, is incorporated herein by reference in its entirety; and PCT application publication WO PCT application publication WO2011 / 034962, published on 28 July 2011, is incorporated herein by reference in its entirety; PCT application publication WO2011 / 139489, published on 26 January 2012, is incorporated herein by reference in its entirety; PCT application publication WO2011 / 139765, published on 8 March 2012, is incorporated herein by reference in its entirety. PCT application publication WO2012 / 027710, published on 18 May 2012, is incorporated herein by reference in its entirety; PCT application publication WO2012 / 170931, published on 21 February 2013, is incorporated herein by reference in its entirety; PCT application publication WO2012 / 170951, published on 25 April 2013, is incorporated herein by reference in its entirety; and PCT application publication WO2013 / 05, published on 25 April 2013, is incorporated herein by reference in its entirety. PCT application 9666 is incorporated herein by reference in its entirety, PCT application publication WO2013 / 059677, published on 25 April 2013, PCT application publication WO2014 / 043715, published on 20 March 2014, is incorporated herein by reference in its entirety, and PCT application publication WO2014 / 059333, published on 17 April 2014, is incorporated herein by reference in its entirety. [Brief explanation of the drawing]

[0017] Novel features of the present invention are described in particular 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 illustrating embodiments in which the principles of the present invention are used, and to the following appended drawings. [Figure 1A] This shows mouse acinar cell necrosis after treatment with TLCS. [Figure 1B] This shows human acinar cell necrosis after treatment with TLCS. [Figure 2A] The histopathological scores for cerulein-induced acute pancreatitis are shown. [Figure 2B] The histopathological scores for TLCS-induced acute pancreatitis are shown. [Figure 2C] The histopathological scores for FAEE-induced acute pancreatitis are shown. [Figure 3A] The IC50 values ​​for N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazine-2-yl)-2-fluoro-6-methylbenzamide ("Compound I") are shown. [Figure 3B] The IC50 measurement values ​​for 2,6-difluoro-N-(1-(4-hydroxy-2-(trifluoromethyl)benzyl)-1H-pyrazole-3-yl)benzamide ("GSK-7975A") are shown. [Figure 4A] This shows calcium uptake in the absence of a CRAC inhibitor. [Figure 4B] This shows calcium uptake in the presence of a CRAC inhibitor. [Figure 5A] This shows calcium influx under the presence of CRAC inhibitor compound I. [Figure 5B] This shows calcium influx in the presence of the CRAC inhibitor GSK-7975A. [Figure 6A] This shows calcium influx in the absence of a CRAC inhibitor. [Figure 6B] This shows the relative calcium influx of CRAC inhibitor compound I and GSK-7975A under certain conditions compared to the control. [Figure 7]This shows the IC50 values ​​of compound I against many cytokines. [Figure 8A] The histopathological scores for various concentrations of compound I are shown. [Figure 8B] This shows the concentration of compound I in the pancreas according to the dose administered. [Figure 9A] The serum amylase levels in mice that did not experience acute pancreatitis (standard) and mice that did experience acute pancreatitis, both with and without CRAC inhibitors, are shown. [Figure 9B] The serum lipase levels in mice that did not experience acute pancreatitis (standard) and mice that did experience acute pancreatitis, both with and without CRAC inhibitors, are shown. [Figure 10] The histopathological scores of mice treated therapeutically and prophylactically at the time of induction of acute pancreatitis are shown. [Figure 11] This shows TLCS-induced calcium levels. [Figure 12] This shows the level of amylase release from mouse acinar cells. [Modes for carrying out the invention]

[0018] The methods and compositions disclosed herein are used to regulate intracellular calcium to improve or prevent symptoms of pancreatitis. In some embodiments, pancreatitis is acute pancreatitis. In some embodiments, pancreatitis is chronic pancreatitis. In some embodiments, the methods and compositions disclosed herein are used to regulate intracellular calcium to improve or prevent symptoms of viral diseases. In some embodiments, viral diseases are hemorrhagic fever viruses. In some embodiments, hemorrhagic fever viruses are arenaviruses, filoviruses, bunyaviruses, flaviviruses, rhabdoviruses, or combinations 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 regulate intracellular calcium to improve or prevent symptoms of Th17-induced diseases. In some embodiments, Th17-induced diseases are inflammatory diseases. In a further embodiment, Th17-induced diseases are autoimmune disorders. 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 protein and Orai protein. 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 crucial role in cell function and survival. For example, calcium is a vital component in the introduction of signals into and within cells. Cellular responses to growth factors, neurotransmitters, hormones, and various other signaling molecules are initiated via calcium-dependent processes.

[0020] In fact, all cell types, in some way, use cytoplasmic Ca to regulate cellular functions or trigger specific reactions. 2+ Depends on signal generation. Cytoplasmic Ca 2+ Signaling controls many cellular functions, ranging from short-term responses such as contraction and secretion to the longer-term regulation of cell growth and proliferation. Typically, such signals involve Ca2+ from intracellular stores such as the endoplasmic reticulum (ER). 2+ The release of Ca across the plasma membrane 2+ It is related to some combination of influx. In one example, cell activation begins with agonist binding to a surface membrane receptor, which is then bound to phospholipase C (PLC) via a G protein mechanism. PLC activation leads to the production of inositol 1,4,5-triphosphate (IP3), which in turn activates IP3 receptors, causing Ca to be released from the ER. 2+ This causes the release of ER Ca. 2+ A decrease (fall) in this signaling pathway activates store-sensitive calcium (SOC) channels in the plasma membrane.

[0021] Store-sensitive calcium (SOC) influx is not limited, but intracellular Ca 2+This is a process in cell physiology that controls the aforementioned diverse functions, such as cell refilling (Putney et al. Cell, 75, 199-201, 1993), enzyme activation (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 (PACs), epithelial and ductal cells of other glands (e.g., salivary glands), endothelial cells, and endothelial progenitor cells, SOC influx occurs via calcium-releasing activated calcium (CRAC) channels, which are a type of SOC channel.

[0022] The calcium influx mechanism has been referred to as store-sensitive calcium influx (SOCE). Interstitial 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 combined regulatory systems involved in controlling intracellular calcium concentration and movement. Intracellular calcium homeostasis is achieved, at least partially, within the cell by calcium binding, by the movement of calcium to and from the plasma membrane, and by the movement of calcium across the 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 carried out by specific proteins. For example, calcium from the extracellular space can enter the cell through various calcium channels and sodium / calcium exchangers and is actively extruded from the cell by calcium pumps and sodium / calcium exchangers. Calcium can also be released from internal stores, pass through inositol trisphosphate or ryanodine receptors, and be taken up by such organelles by calcium pumps.

[0025] Calcium can enter the cell by any of various normal classifications of calcium, which include, but are not limited to, voltage-operated calcium (VOC) channels, store-operated calcium (SOC) channels, and sodium / calcium exchangers operating in the reverse mode. VOC channels are activated by membrane depolarization, are found in excitable cells such as nerves and muscles, and are mostly not found in non-excitable cells. Under some conditions, Ca 2+ can enter the cell via the Na+-Ca 2+ exchanger operating in the reverse mode.

[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 concentration is tightly regulated in mammalian cells at a typically estimated quiescent level of approximately 0.1 μM, while extracellular calcium concentration is typically around 2 mM. This tight regulation facilitates the introduction of signals into and within cells via transient calcium flows across the plasma membrane and organelle membranes. Cells have various intracellular calcium transport and buffering systems that play a role in forming intracellular calcium signals and maintaining low quiescent cytoplasmic calcium concentrations. In quiescent cells, the main components involved in maintaining basal calcium concentration are calcium pumps and leakage pathways in both the endoplasmic reticulum and the plasma membrane. Disruption of quiescent cytoplasmic calcium concentration can affect the transmission of calcium-dependent signals and lead to defects in many cellular processes. For example, cell proliferation is related to the extension of calcium signaling sequences. Other cellular processes involved in calcium signaling include, but are not limited to, secretion, transcription factor signaling, and fertilization.

[0028] The cell surface receptor that activates phospholipase C (PLC) absorbs cytoplasmic calcium from intracellular and extracellular sources. 2+ Create a signal. [Ca 2+ The initial transient increase in ]i (intracellular calcium concentration) is triggered by PLC products in the ER, inositol-1,4,5-trisphosphate (IP3), and the opening of IP3 receptors, resulting in Ca from the endoplasmic reticulum (ER). 2+ This is due to the release of (Streb et al. Nature, 306, 67-69, 1983). Subsequently, slow-release Ca across the plasma membrane. 2+ The subsequent stages after influx occur in the plasma membrane via specialized store-sensitive calcium (SOC) channels (in the case of non-excitable cells such as immune PAC cells, the SOC channel is a calcium-releasing activated calcium (CRAC) channel). 2+ Inflow (SOCE) is Ca 2+ Emptying the store itself helps to replenish the store by creating Ca in the plasma membrane. 2+SOCE is a process that activates the channel (Putney, Cell Calcium, 7, 1-12, 1986; Parekh et al., Physiol. Rev. 757-810; 2005). SOCE is a process that refills the store with Ca 2+ Not only does it simply provide nutrients, but it also controls essential functions such as gene expression, cell metabolism, and exocytosis, providing sustained-release Ca 2+ It can generate signals (Parekh and Putney, Physiol. Rev. 85, 757-810 (2005)).

[0029] In lymphocytes and mast cells, activation of the antigen or Fc receptor, respectively, successively triggers Ca through CRAC channels in the plasma membrane. 2+ Ca from intracellular storage leads to influx. 2+ This causes the release of intracellular Ca 2+The subsequent increase in NFAT activates calcineurin, a phosphatase that modulates the transcription factor NFAT. In quiescent cells, NFAT is phosphorylated and resides in the cytoplasm, but when dephosphorylated by calcineurin, NFAT moves to the nucleus and activates different gene programs depending on the stimulus condition and cell type. In response to infection and during transplant rejection, NFAT combines with the transcription factor AP-1 (Fos-Jun) in the nucleus of "effector" T cells, thereby transactivating cytokine genes, genes that regulate T cell proliferation, and genes that organize 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 and activates a transcriptional program known as "anergy" that 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 that suppress autoimmunity mediated by self-reactive effector T cells, NFAT pairs 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) performs various processes. The ER is Ca 2+ Sink and agonist-sensitive Ca 2+ It serves as both a store and a lumen, and protein folding / processing occurs within its lumen. In the latter case, numerous Ca 2+Dependent chaperone proteins ensure that newly synthesized proteins are correctly folded and delivered to their appropriate destinations. The ER is also involved in vesicle transport, stress signaling, regulation of cholesterol metabolism, and apoptosis. Many of these processes involve Ca in the lumen. 2+ This requires, and protein misfolding, ER stress response, and apoptosis are all prolonged Ca 2+ It can be triggered by the depletion of ER. It is caused by a finite amount of Ca 2+ Because it includes, ER Ca 2+ The contents of Ca during stimulation 2+ It is clear that it must decrease after the release of . However, in order to preserve the functional integrity of the ER, Ca 2+ It is important that the contents do not fall too low, or at least are maintained at a low level. Therefore, Ca 2+ ER supplementation by is a central treatment for all eukaryotic cells. ER Ca 2+ The decrease in contents in the plasma membrane leads to the storage of sensitive Ca 2+ Because it activates the channel, this Ca 2+ The primary function of the entry pathway is the ER Ca, which is necessary for proper protein synthesis and folding. 2+ It is thought to be a maintenance of the level. However, the store sensitivity Ca 2+ Channels have other important roles.

[0031] Understanding store-sensitive calcium influx is that the process of emptying the store is Ca 2+ Release activated Ca 2+ Ca in mast cells, called current or ICRAC 2+ This was obtained through electrophysiological testing to ensure that the current is activated. ICRAC is not activated by voltage, and internally rectifies and Ca 2+ It is remarkably selective. It is found primarily in various cell types of hematopoietic origin. ICRAC is not the only store-sensitive current; currently, store-sensitive influx has different properties in different cell types.2+ It is clear that it encompasses a family of permeable channels. ICRAC is the first store-sensitive Ca described. 2+ It is an electric current and remains a popular model for studying store-sensitive inflow.

[0032] Store-sensitive calcium channels are ER Ca 2+ It can be activated by any procedure that empties the store, and how the store is emptied is not considered important; the net effect is on store-sensitive Ca 2+ It is an activation of inflow. Physiologically, emptying the store is an activation of IP3 or other Ca 2+ Increased level of release signal, followed by Ca from store 2+ It is triggered by release. However, there are various other ways to empty the store. These methods include: 1) Elevation of IP3 in the cytosol (after receptor stimulation, or after dialysis of the cytosol with IP3 itself or related allogenes such as the non-metabolic analog Ins(2,4,5)P3); 2) Ca to make the ER membrane permeable 2+ Application of ionophores (e.g., ionomycin); 3) Ca leaks from the store, thus preventing the store from refilling. 2+ Chelates high concentrations of Ca 2+ Cytoplasmic dialysis using chelating agents (e.g., EGTA or BAPTA); 4) Sarcoplasmic / endoplasmic reticulum Ca such as thapsigardin, cyclopiazonic acid, and di-tert-butylhydroquinone 2+ - Exposure to ATPase (SERCA) inhibitors; 5) Sensitization of IP3 receptors to quiescent 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 filling of chelating agents into stores. Through mass action, TPEN stores the total amount of Ca 2+ Without changing the free luminal Ca2+ The concentration is reduced, thereby generating a signal that depends on the depletion of the store.

[0033] This method of emptying the store is not without potential problems. Store sensitivity Ca 2+ An important function of inflow is Ca within the store. 2+ This is a decrease in contents, and cytoplasmic Ca activates the channel. 2+ It is not a subsequent increase in concentration. However, ionomycin and SERCA pump blockers typically result in cytoplasmic Ca as a result of store depletion. 2+ This causes an increase in concentration, such as Ca 2+ The rise in Ca 2+ Ca is permeable to it. 2+ This can open activated cation channels. One way to avoid such problems is to use high concentrations of Ca such as EGTA or BAPTA. 2+ Chelating agents affect cytoplasmic calcium 2+ This involves using the drug under strongly buffered conditions.

[0034] <Store-sensitive calcium inflow> The release of calcium from intracellular calcium stores, resulting in a decrease in calcium concentration in intracellular calcium stores such as the endoplasmic reticulum, signals the influx of calcium from the extracellular medium into the cell. This calcium influx results in a sustained "plateau" of cytoplasmic calcium concentration and is usually independent of voltage-gated plasma membrane channels and does not involve calcium-mediated activation of calcium channels. This calcium influx mechanism is referred to as capacitive calcium influx (CCE), calcium release activation, store-sensitive, or depletion-operated calcium influx. Store-sensitive calcium influx can be recorded as an ionic current with unique characteristics. This current is I SOC (Store-sensitive current) or I CRAC This is called the calcium release activation current.

[0035] Electrophysiological analysis of store-sensitive or calcium-releasing activated currents has revealed distinct biophysical properties of these currents (see, e.g., Parekh and Penner (1997) Physiol. Rev. 77:901-930). For example, currents can be activated by the depletion of intracellular calcium stores (by non-physiological activators such as thapsigardin, CPA, ionomycin, and BAPTA, as well as physiological activators such as IP3), are selective to divalent cations such as calcium rather than monovalent ions in physiological solutions or under physiological conditions, are affected by changes in cytoplasmic calcium concentration, and can exhibit altered selectivity and conductivity in the presence of low extracellular concentrations of divalent cations. Currents can also be blocked or enhanced by 2-APB (in a concentration-dependent manner), blocked by SKF96365 and Gd3+, and can usually be described as calcium currents that are not strictly voltage-dependent.

[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, specifically Ca2+, which has very low conductivity. 2+ It includes high selectivity for cytoplasmic Ca. Furthermore, CRAC channels have been shown to meet stringent criteria for becoming store-sensitive, which is simply cytoplasmic Ca. 2+ Or rather than other messengers generated by PLC, Ca in ER 2+ This is activation due to a decrease in (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-sensitive calcium influx by intracellular calcium stores> Store-sensitive calcium influx is regulated by the level of calcium in intracellular calcium stores. Intracellular calcium stores may be characterized by sensitivity to agents, which may be physiological or pharmacological, that activate the release of calcium from the stores or inhibit the uptake of calcium into the stores. Different cells have been studied in characterizing intracellular calcium stores, and these stores have been characterized as sensitive to a variety of drugs, including but not limited to IP3 and compounds that affect IP3 receptors, thapsigardin, 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] Calcium accumulation in the storage organelles of the endoplasmic reticulum and sarcoplasmic reticulum (SR; a specialized version of the endoplasmic reticulum in striated muscle) is achieved via sarplasmosis calcium ATPase (SERCA), commonly referred to as the calcium pump. During signaling (i.e., when endoplasmic reticulum channels are activated to release calcium from the endoplasmic reticulum to the cytoplasm), endoplasmic reticulum calcium is replenished by the SERCA pump with cytoplasmic calcium that has entered the cell from the extracellular medium (Yu and Hinkle (2000) J. Biol. Chem. 275:23648-23653; Hofer et al. (1998) EMBO J. 17:1986-1995).

[0039] IP3 and ryanodine receptor-mediated calcium release channels result in the regulated release of calcium from the endoplasmic and sarcoplasmic reticulum into the cytoplasm, which occurs as a result of a transient increase in cytoplasmic calcium concentration. IP3 receptor-mediated calcium release is triggered by IP3 formed by the disruption of plasma membrane phosphoinositides via the action of phospholipase C, which is activated by the binding of an agonist to the receptor or tyrosine kinase bound to the plasma membrane G protein. Lyanodine receptor-mediated calcium release is triggered by an increase in cytoplasmic calcium and is called calcium-induced calcium release (CICR). The activity of the ryanodine receptor (which has affinity for ryanodine and caffeine) may also be regulated by cyclic ADP-ribose.

[0040] Therefore, calcium concentrations in the store and cytoplasm fluctuate. For example, ER free calcium concentration can decrease from 60–400 μM to approximately 1–50 μM when HeLa cells are treated with histamine, i.e., PLC-binding histamine receptor agonists (Miyawaki et al. (1997) Nature 388:882–887). A decrease in intracellular store free calcium concentration activates store-sensitive calcium influx. Thus, store calcium depletion, as well as a concomitant increase in cytosolic calcium concentration, can also regulate store-sensitive calcium influx into cells.

[0041] <Buffering of cytoplasmic calcium> Agonist activation of signaling processes within cells can involve, for example, a dramatic increase in endoplasmic reticulum (ER) calcium permeability across the plasma membrane, mediated by the opening of IP3 receptor channels and store-sensitive calcium influx. Such an increase in calcium permeability is associated with an increase in cytosolic calcium concentration, which can be separated into two components: a "spike" of calcium release from the ER during IP3 receptor activation, and a plateau phase, a sustained increase in calcium concentration resulting from the influx of calcium from extracellular medium into the cytoplasm. Following stimulation, the quiescent intracellular free calcium concentration of approximately 100 nM can increase overall to more than 1 μM, and more significantly in the cellular microdomains. Cells regulate these calcium signals with endogenous calcium buffers, including physiological buffering by organelles such as mitochondria, the ER, and the Golgi apparatus. Mitochondrial uptake of calcium via monotransporters in the inner membrane occurs due to a large negative mitochondrial membrane potential, and the accumulated calcium is slowly released via sodium-dependent and sodium-independent exchangers, and under certain conditions, through membrane permeable transition pores (PTPs). Therefore, mitochondria can act as calcium buffers by taking up calcium during periods of cellular activation and then slowly releasing it afterward. Calcium uptake into the endoplasmic reticulum is regulated by sarcoplasmic and endoplasmic reticulum calcium ATPases (SERCA). Calcium uptake into the Golgi apparatus is mediated by P-type calcium transport ATPases (PMR1 / ATP2C1). In addition, there is evidence that significant amounts of calcium released after IP3 receptor activation are pushed out of the cell by the action of plasma membrane calcium ATPases. For example, plasma membrane calcium ATPases provide the dominant 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.In addition, the cytosol contains calcium buffering proteins that regulate calcium spikes and assist in the redistribution of calcium ions. Therefore, proteins and other molecules involved in any of these and other mechanisms by which cytosolic calcium concentration can be reduced are proteins that are involved in, participate in, and / or provide cytoplasmic calcium buffering. Thus, cytoplasmic calcium buffering is related to the slow-release calcium influx through SOC channels, or Ca. 2+ During the period of sudden release, cytoplasmic Ca 2+ Helps regulate levels. Cytoplasmic Ca 2+ SOCE is deactivated by increasing the level or refilling the store.

[0042] <Events mediated by downstream calcium inflow> In addition to intracellular changes in calcium stores, store-sensitive calcium influx affects multiple events, either due to or in addition to changes in store sensitivity. For example, Ca 2+ The influx of calcium results in the activation of many calmodulin-dependent enzymes, including the serine phosphatase calcineurin. Activation of calcineurin due to increased intracellular calcium results in acute secretory processes, such as mast cell degranulation. Activated mast cells release pre-formed granules containing enzymes such as histamine, heparin, TNFα, and β-hexosaminidase. Several cellular events, such as B cell and T cell proliferation, require sustained calcineurin signaling that demands a sustained increase in intracellular calcium. Many transcription factors are regulated by calcineurin, including NFAT (nuclear factor of activated T cells), MEF2, and NFκB. The NFAT transcription factor plays a crucial role in many cell types, including immune cells. In immune cells, NFAT mediates the transcription of many molecules, including cytokines, chemogens, and cell surface receptors. Transcriptional elements for NFAT were found in cytokine promoters such as IL-2, IL-3, IL-4, IL-5, IL-8, and IL-13, as well as in tumor necrosis factor alpha (TNFα), granulocyte colony-stimulating factor (G-CSF), and γ-interferon (γ-IFN).

[0043] The activity of the NFAT protein is regulated by the phosphorylation levels of both calcineurin and NFAT kinase, which are successively regulated by these two kinases. Activation of calcineurin due to increased intracellular calcium concentration results in the dephosphorylation and nuclear influx of NFAT. Rephosphorylation of NFAT covers its nuclear localization sequence, preventing its entry into the nucleus. Due to its strong dependence on calcineurin-mediated dephosphorylation for localization and activity, NFAT is a highly sensitive indicator of intracellular free calcium levels.

[0044] <Calcium channel inhibitors> This specification discloses numerous calcium channel inhibitors corresponding to 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 containing the STIM1 protein. In some embodiments, the calcium channel inhibitor inhibits channels containing the Orai1 protein. In some embodiments, the calcium channel inhibitor inhibits channels containing the Orai2 protein.

[0045] In some embodiments, the compound is a compound having the following structure:

[0046] [ka] Alternatively, the compound may be a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the compound is selected from a list of compounds consisting of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazine-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)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, intracellular calcium signaling inhibitors include the following compounds: N-(5-(6-ethoxy-4-methylpyridine-3-yl)pyrazine-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazole-5-yl)pyridine-2-yl)-3,5-difluoroisonicotinamide, N-(4-(1-ethyl-3-(thiazole-2-yl)-1H-pyrazole-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)pyrazine-2-yl)-2,4,6-trifluoro Robenzuamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)phenyl)-1H-pyrazole-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazole-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazole-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazole-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)-N-((3-methylisothiazol-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxyno[2,3-b]pyridine-6-yl)pyridine-2-yl)-2,6-difluorobenz Amides, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazole-2-yl)-1H-pyrazole-5-yl)pyrimidine-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazole-2-yl)-1H-pyrazole-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)-N-(2,4,6-trifluorobenzyl)pyridine-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole (5-yl)pyridine-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazole-6-yl)pyrazine-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridine-3-yl)thiazole-2-yl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)pyridine-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3- Selected from ruoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazole-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable prodrugs thereof.

[0047] <Calcium signaling and pancreatic health> Calcium signaling is central to the activity of a healthy pancreas. Foods stimulate the release of acetylcholine (ACh) and cholecystokinin (CCK), which interact with receptors bound to phospholipase C (PLC) on pancreatic acinar cells (PACs). In healthy PACs, the receptors for ACh or CCK trigger the formation of IP3, 1,4,5-inositol triphosphate, which spreads to the apical region and transmits calcium in a controlled, pulsatile manner. 2+ Stimulates IP3 receptors on the endoplasmic reticulum (ER) to release Ca. 2+ Oscillation stimulates the release of enzyme precursors (proenzymes) into the pancreatic duct. Over time, ER Ca 2+ This needs to be replenished, which is achieved by the gentle activation of CRAC channels in the basolateral region of the cell.

[0048] In certain situations (e.g., alcoholism or excessive drinking, gallstones), fatty acid ethyl esters (FAEEs) formed from alcohol, or bile acids accumulated by gallstones, diffuse into the PAC. Within the PAC, FAEEs and bile acids are released into the ER via activation of the IP3 receptor. 2+ This triggers a massive release of calcium. Overstimulation of CCK receptors also triggers a massive release of stubborn calcium from the ER store. 2+ It can induce release. Ca 2+ Emptying the store leads to hyperactivation of the CRAC channel, which in turn leads to Ca 2+ This causes an excessive influx of large amounts of Ca. 2+Influx causes the release of enzymes from zymogen granules and improper activation of intracellular trypsin, which subsequently activates other pancreatic digestive enzymes and leads to pancreatic autodigestion and necrosis, which can be blocked by CRAC channel inhibitors such as Compound I, GSK-7975A, N-(5-(2,5-dimethylbenzo[d]oxazole-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-pyrazole-5-yl)phenyl)benzamide (Compound III).

[0049] If left untreated, the improper release and activation of digestive enzymes such as trypsin from Zymogen granules can lead to autodigestion by pancreatic cells, resulting in pancreatitis. As mentioned 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 radiating down the back, nausea, and vomiting that worsens with eating. Depending on the severity of the disease, internal bleeding may also occur. Blood pressure, heart rate, and respiratory rate are frequently elevated, although dehydration may lead to a decrease in blood pressure rather than an increase. The abdomen is frequently tender, but not as painful as pain in the pancreas itself. Reflex bowel paralysis is common in pancreatitis, and fever or jaundice is not uncommon. Common symptoms and signs of pancreatitis include severe upper abdominal pain (epigastric pain) radiating down the back, nausea, vomiting, loss of appetite, fever, chills, hemodynamic instability (including shock), tachycardia (rapid heartbeat), respiratory distress, and peritonitis.

[0051] Less commonly observed symptoms indicating severe disease include many medical "signs" of severe abdominal distress: Gray-Turner sign (hemorrhagic discoloration of the flank), Karen's sign (hemorrhagic discoloration of the umbilicus), pleural exudation (fluid in the base of the pleural cavity), Grünwald's sign (patchy hemorrhage around the umbilicus, appearance of large contusions due to local toxic lesions of the blood vessels), Korte's sign (pain or pain in the area where the head of the pancreas is located (upper abdomen, i.e., 6-7 cm above the umbilicus) Mayo-Robson signs include resistance, Kamenchik's sign (pain upon pressure below the xiphoid process), and the Mayo-Robson point (a point on the boundary between the inner two-thirds and the outer one-third of the line representing the left upper abdomen, where tenderness to pressure indicates pancreatic disease; at this point, the tail of the pancreas protrudes above the abdominal wall).

[0052] People suffering from pancreatitis may exhibit some, all, or even a few of the aforementioned symptoms. In some cases, abdominal pain may be the only symptom of the disease.

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

[0054] As many as 80 percent of pancreatitis cases 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, many other causes of pancreatitis exist. Some medications may also be associated with pancreatitis. Examples of medications associated with pancreatitis include corticosteroids such as prednisolone, HIV drugs such as didanosine and pentamidine, diuretics, anticonvulsants such as valproic acid, chemotherapeutic agents such as L-asparaginase and azathioprine, estrogens, drugs that raise blood triglycerides, statins such as cholesterol-lowering statins, antiglyceridens 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 amplified events of pancreatitis may also be incidentally associated with pancreatitis. Examples include statins in dyslipidemia and gliptins in diabetes. In addition, several atypical antipsychotics, such as clozapine, risperidone, and olanzapine, can also cause pancreatitis. This list is not exhaustive.

[0056] Non-medicinal causes of pancreatitis are also known. For example, the genotype of pancreatitis is known to result in the activation of trypsinogen in the pancreas, leading to autodigestion. Genes associated with hereditary pancreatitis include Trypsin1, which codes for trypsinogen; SPINK1, which codes for trypsin inhibitors; and transmembrane conductivity regulators in cystic fibrosis.

[0057] Other common non-medical causes of pancreatitis include trauma, mumps, autoimmune diseases, hypertensive calcium, hypothermia, and experience with endoscopic retrograde cholangiopancreatography (ERCP). Pancreatic ductal fusion anomaly is a common congenital malformation of the pancreas that can underlie some recurrent cases. Perforating ulcers are also associated with pancreatitis. Type 2 diabetes has been associated with a 2.8 times higher risk of progression of pancreatic symptoms. Further diseases associated with pancreatitis include pancreatic cancer, intraductal stones, vasculitis (inflammation of microvessels in the pancreas), coxsackievirus infection, and porphyria, particularly acute intermittent porphyria and myeloid protoporphyria. In some cases, pregnancy is also associated with pancreatitis. Repeated marathon running, anorexia, and bulemia, as well as fat necrosis, pancreatic cystic fibrosis, and scorpion venom are also associated with some cases of pancreatitis.

[0058] Many infectious agents are associated with pancreatitis. Examples include, in particular, viral infections caused by viruses such as cytomegalovirus, hepatitis B, herpes simplex virus, mumps lubravirus, and varicella-zoster virus; bacterial infections caused by bacteria such as Legionella, Leptospira, Mycoplasma, or Salmonella; fungal infections caused by fungi such as Aspergillus; or parasitic infections caused by nematodes of the Ascaris genus, or by Cryptosporidium and Toxoplasma apicomplexa alveolata.

[0059] "GETSMASHED," a memo aid for medical students, 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, valproic acid).

[0060] Pancreatitis can also be idiopathic, in which case the cause is not identified.

[0061] <Classification of Pancreatitis> Pancreatitis, particularly acute pancreatitis, is frequently classified as "mild," "moderate," or "severe" depending on the primary response to cellular damage. All of these classifications are typically characterized by the misactivation of pancreatic enzyme precursors, such as trypsinogen, within the pancreas, usually due to co-localization of trypsinogen with cathepsin, a trypsinogen maturation enzyme. 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 those with severe acute pancreatitis suffer from persistent (>48 hours) organ failure.

[0062] In response to the aforementioned issues, the pancreas may directly synthesize inflammatory mediators such as TNF-α and IL-1, or activate the immune system, in connection with inflammatory responses and the recruitment of neutrophils to the pancreas, or through necrosis and leakage of cellular components. The inflammatory response may also lead to secondary symptoms of pancreatitis, such as hypovolemia due to 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 lesions in pancreatic fat, and vascular necrosis (hemorrhage) resulting from intrapancreatic activation of pancreatic enzymes. Lipase activation can also lead to necrosis of adipose tissue in the pancreatic interstitium and peripancreatic space, as well as vascular damage. Digestion of vascular walls results in thrombosis and hemorrhage. Inflammatory infiltrates are abundant in neutrophils. Due to the absence of a pancreas capsule, inflammation and necrosis can spread to include layers of fascia immediately surrounding the pancreas.

[0064] Chronic pancreatitis is persistent pancreatitis that alters the normal tissue and function of the organ. Chronic pancreatitis may be associated with the onset of acute pancreatitis, persistent abdominal pain, or digestive problems. Patients with chronic pancreatitis usually exhibit persistent abdominal pain or malabsorption of fats in food. Pain during food intake, especially with fatty or high-protein foods, is common. Weight loss due to malabsorption 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, pancreatic cystic fibrosis, and genetic defects are generally associated with chronic pancreatitis in terms of trypsinogen handling and stability.

[0067] Chronic pancreatitis is typically diagnosed based on examinations of the structure and function of the pancreas. Serum amylase and lipase may be moderately elevated or not elevated in cases of chronic pancreatitis, due to uncertain levels of germ cell damage. Elevated lipase is more likely to be found among the two. Amylase and lipase have almost always been elevated in acute disease, along with elevated CRP, an inflammatory marker, which broadly follows the severity of the disease.

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

[0069] Many additional tests are available for assays for chronic pancreatitis. Elevated serum bilirubin and alkaline phosphatase levels indicate chronic pancreatitis, and may also indicate edema, fibrosis, or stricture of the common bile duct due to cancer. Autoimmune-associated chronic pancreatitis is accompanied by elevated levels of ESR, IgG4, rheumatoid factor, ANA, and anti-smooth muscle antibodies, and any of these assays may indicate chronic pancreatitis in humans. The classic symptoms of chronic pancreatitis, namely steatorrhea or malabsorption, may be diagnosed by two different tests: Sudan chemical staining of the excretion of 7 grams or more of stool or fecal fat over a 24-hour period on a 100 g fatty diet. To check for exocrine gland dysfunction of the pancreas, a typical, highly sensitive, and specific test is the measurement of fecal elastase performed on a single stool sample; values ​​less than 200 μg / g indicate pancreatic dysfunction.

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

[0071] Numerous cited studies discuss the severity of pancreatitis, each incorporated herein by citation: 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] <Treatmental improvement of pancreatitis> This specification discloses compositions and methods for the therapeutic improvement of pancreatitis and its symptoms, including through the administration of calcium channel inhibitors such as CRAC inhibitors. In some embodiments, pancreatitis is acute pancreatitis. In some embodiments, pancreatitis is chronic pancreatitis. In some embodiments, methods for improving the symptoms of pancreatitis in humans are disclosed. In some embodiments, a method for improving the symptoms of pancreatitis in humans is disclosed, the method comprising the steps of identifying a person in need of improvement of the symptoms of pancreatitis, and administering to the person an intracellular calcium signaling inhibitor in a dose sufficient to improve the symptoms.

[0073] The aforementioned human may be identified using, for example, common tests for pancreatitis symptoms such as 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, a human is identified as a person in need of improvement of pancreatitis symptoms by having a BISAP score of 5, 4, 3, 2, or 1. In some embodiments, a human is identified as having a BISAP score of 2. In some embodiments, a human is identified as having a BISAP score of 3. In some embodiments, a human is identified as having a BISAP score of 4. In some embodiments, a human is identified as having a BISAP score of 5. In some embodiments, a human is identified as having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 pancreatitis symptoms, such as the pancreatitis symptoms disclosed herein. In some embodiments, the subject is a non-human mammal, not a human.

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

[0075] Symptoms may include at least one of the following: abdominal pain, increased blood amylase levels, increased blood lipase levels, pancreatic dilation, nausea, vomiting, internal bleeding, intestinal paralysis, fever, jaundice, weight loss, and increased heart rate. Symptoms may include premature digestive enzyme activation, which 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, improvement of pancreatitis symptoms further comprises administering an analgesic drug. In some embodiments, improvement of pancreatitis symptoms further comprises administering an analgesic drug comprising opiates. In some embodiments, improvement of pancreatitis symptoms further comprises administering an analgesic drug comprising morphine. In some embodiments, improvement of pancreatitis symptoms further comprises administering an analgesic drug comprising fentanyl. In some embodiments, improvement of pancreatitis symptoms further comprises administering an analgesic drug comprising tramadol. In some embodiments, improvement of pancreatitis symptoms further comprises administering an analgesic drug comprising meperidine.

[0077] In some embodiments, intracellular calcium signaling inhibitors are determined for the compound in in vitro IC 50 It is delivered to achieve tissue level concentrations equal to, equal to, or higher than the value. In some embodiments, the calcium signaling inhibitor is delivered in vitro to achieve the IC25 concentration determined for the compound. 50Values ​​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 It is delivered to achieve tissue-level concentrations of 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, calcium signaling inhibitors are determined in vitro for the compound. 50 It is 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, or any non-integer within the aforementioned ranges.

[0079] In some embodiments, the calcium signaling inhibitor is available in concentrations of 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, and 25 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 It is delivered to achieve tissue-level concentrations of μM, 83μM, 84μM, 85μM, 86μM, 87μM, 88μM, 89μM, 90μM, 91μM, 92μM, 93μM, 94μM, 95μM, 96μM, 97μM, 98μM, 99μM, 100μM, or any non-integer multiple ranging from approximately 1μM to approximately 100μM.

[0080] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 within the aforementioned ranges.

[0081] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 within the aforementioned ranges.

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

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

[0084] <Preventive treatment and improvement of acute and chronic pancreatitis> This specification discloses compositions and methods for the prophylactic improvement of acute pancreatitis and its symptoms, including through the administration of calcium channel inhibitors such as CRAC inhibitors. In some embodiments, methods for improving the symptoms of pancreatitis in humans are disclosed. In some embodiments, methods for improving the symptoms of pancreatitis in humans are disclosed, the methods comprising the steps of identifying a person in need of prophylactic improvement of the symptoms of pancreatitis, and administering to the person an intracellular calcium signaling inhibitor in a dose sufficient to prophylactically improve the symptoms.

[0085] 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, improvement of pancreatitis symptoms further comprises administering analgesic drugs such as opiates. Morphine is a typical analgesic in some embodiments.

[0086] In some embodiments, intracellular calcium signaling inhibitors are determined for the compound in in vitro IC 50 It is delivered to achieve tissue level concentrations equal to, equal to, or higher than the value. In some embodiments, the calcium signaling inhibitor is delivered in vitro to achieve the IC25 concentration determined for the compound. 50 Values ​​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 It is delivered to achieve tissue-level concentrations of 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, calcium signaling inhibitors are determined in vitro for the compound. 50 It is 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, or any non-integer within the aforementioned ranges.

[0088] In some embodiments, the calcium signaling inhibitor is available in concentrations of 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, and 25 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 It is delivered to achieve tissue-level concentrations of μM, 83μM, 84μM, 85μM, 86μM, 87μM, 88μM, 89μM, 90μM, 91μM, 92μM, 93μM, 94μM, 95μM, 96μM, 97μM, 98μM, 99μM, 100μM, or any non-integer multiple ranging from approximately 1μM to approximately 100μM.

[0089] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 within the aforementioned ranges.

[0090] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 within the aforementioned ranges.

[0091] In some embodiments, the method includes prophylactically improving the symptoms of acute pancreatitis. In some embodiments, the method includes prophylactically improving the symptoms of chronic pancreatitis.

[0092] Prophylactic improvement of pancreatitis symptoms may include a reduction in the severity, likelihood, or duration of at least one symptom of pancreatitis. Prophylactic improvement of pancreatitis symptoms may include reducing the severity, likelihood, or duration of at least one symptom of pancreatitis to the point at which at least one symptom of pancreatitis no longer occurs in humans. In some embodiments, prophylactic improvement of pancreatitis symptoms includes reducing the severity, likelihood, or duration of 2, 3, 4, 5, 6, 7, 8, 9, or more symptoms of pancreatitis, and includes reducing the severity, likelihood, or duration of all symptoms of human pancreatitis, such as the symptoms of pancreatitis disclosed herein. In some embodiments, the subjects are non-human mammals, not humans.

[0093] In some embodiments, a person is diagnosed with gallstones. In some embodiments, the person exhibits symptoms of gallstones, such as pain, for example, severe pain in the upper right side of the abdomen, and / or nausea and vomiting, which can 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, a person suffers from alcoholism. In some embodiments, a person suffers from chronic alcohol consumption. In some embodiments, a person suffers from at least one case of acute alcoholism.

[0095] In some embodiments, a human is exposed to a drug regimen comprising at least one of the following: a steroid such as a corticosteroid; prednisolone; an HIV drug; didanosine; pentamidine; a diuretic; valproic acid; L-asparaginase; azathioprine; estrogen; a statin such as a cholesterol-lowering statin; a hyperglycemic agent; a glipine such as metformin, vildaglipin, and sitaglipin; an atypical antipsychotic; clozapine; risperidone; and olanzapine.

[0096] In some embodiments, a human is identified as having a pancreatitis genotype. In some embodiments, a human has a mutant allele of Trypsin1 associated with inherited pancreatitis. In some embodiments, a human has a mutant enzyme of trypsinogen associated with pancreatitis. In some embodiments, a human has a mutant allele of SPINK1 associated with inherited pancreatitis. In some embodiments, a human has a mutant allele of a cystic fibrosis membrane conduction rate regulator associated with inherited pancreatitis.

[0097] In some embodiments, humans suffer from hypertensive calcium, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), split pancreas, congenital pancreatic malformations, type 2 diabetes, pancreatic cancer, intraductal stones, vasculitis, inflammation of microvascular tissue in the pancreas, coxsackievirus infection, and at least one of the Porphyra species, such as acute intermittent porphyria and myeloid protoporphyria.

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

[0099] In some embodiments, the health status of the human body is affected by at least one of the following: coxsackievirus, cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella, Leptospira, Mycoplasma, Salmonella, Aspergillus fungus, Ascaris parasite, Cryptosporidium cells, and Toxoplasma cells.

[0100] <Concomitant administration with medications related to pancreatitis> This specification discloses compositions and administration regimens for the combined administration of calcium channel inhibitors and drugs associated with pancreatitis. In some embodiments, the administration regimen includes the administration of a drug associated with a negative effect on pancreatic activity to an individual, and the administration of an intracellular calcium signaling inhibitor.

[0101] In some embodiments, the drugs associated with a negative effect on pancreatic activity are drugs selected from the following list: steroids such as corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antihyperglycemic agents, metformin, glipins such as vildaglipin and sitaglipin, atypical antipsychotics, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid.

[0102] In some embodiments, the intracellular calcium signaling inhibitor is a SOC inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC inhibitor. A typical CRAC inhibitor includes compound I. A typical CRAC inhibitor includes GSK-7975A. A typical CRAC inhibitor includes compound II. A typical CRAC inhibitor includes compound III.

[0103] In some embodiments, the administration regimen includes the administration of a calcium channel inhibitor, such as a CRAC inhibitor, including at least one of Compound I, GSK 7975A, Compound II, and Compound III, in conjunction with a drug associated with a negative effect on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, including 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 effect on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, including 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 effect on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, including at least one of Compound I, GSK 7975A, Compound II, and Compound III, is administered concurrently with the administration of a drug associated with a negative effect on pancreatic activity. In some embodiments, calcium channel inhibitors, such as CRAC inhibitors, including at least one of Compound I, GSK 7975A, Compound II, and Compound III, are administered in a dosing regimen pattern independent of the dosing pattern for drugs associated with negative effects on pancreatic activity. In some embodiments, calcium channel inhibitors, such as CRAC inhibitors, including at least one of Compound I, GSK 7975A, Compound II, and Compound III, are administered via the same delivery route, such as orally or intravenously, as drugs associated with negative effects on pancreatic activity. In some embodiments, calcium channel inhibitors, such as CRAC inhibitors, including at least one of Compound I, GSK 7975A, Compound II, and Compound III, are administered via a different dosing route than drugs associated with negative effects on pancreatic activity.In some embodiments, calcium channel inhibitors, such as CRAC inhibitors, including at least one of Compound I, GSK 7975A, Compound II, and Compound III, are administered to a person receiving a drug associated with a negative effect on pancreatic activity only immediately after the person shows at least one sign of the drug's effect associated with a negative effect on pancreatic activity, for example, through an increase in blood amylase activity or the onset of at least one of the pancreatitis symptoms disclosed herein. In some embodiments, calcium channel inhibitors, such as CRAC inhibitors, including at least one of Compound I, GSK 7975A, Compound II, and Compound III, are administered to a person receiving a drug associated with a negative effect on pancreatic activity in a person who shows at least one sign of the drug's effect associated with a negative effect on pancreatic activity, for example, through an increase in blood amylase activity or the onset of at least one of the pancreatitis symptoms disclosed herein, or in the absence of any evidence from such person.

[0104] In some embodiments, calcium channel inhibitors, such as CRAC inhibitors, including at least one of Compound I, GSK 7975A, Compound II, and Compound III, are administered in a single composition comprising the administration of a drug associated with a negative effect on pancreatic activity. Accordingly, some embodiments disclosed herein relate to compositions comprising an intracellular calcium signaling inhibitor and at least one drug associated with a negative effect on pancreatic activity. In some embodiments, the at least one drug is selected from the following list: steroids such as corticosteroids, prednisolone, HIV drugs, didanosine, pentamidine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycerides, metformin, glipins such as vildaglipin and sitaglipin, atypical antipsychotics, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid.

[0105] In some embodiments, the intracellular calcium signaling inhibitor of the composition is a 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, intracellular calcium signaling inhibitors are determined to be effective in vitro against compounds. 50 It is delivered to achieve tissue-level concentrations equal to, near, or exceeding the value. In some embodiments, intracellular calcium signaling inhibitors are used to determine the in vitro IC25 of 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 It is delivered to achieve tissue-level concentrations of 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 in the range from 1x to 100x.

[0107] In some embodiments, intracellular calcium signaling inhibitors are determined to be effective in vitro against compounds. 50The values ​​are delivered to achieve tissue-level concentrations that are 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, or non-integer values ​​within the aforementioned ranges.

[0108] In some embodiments, the intracellular calcium signaling inhibitor is available in concentrations of 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 2 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, It is delivered to achieve tissue-level concentrations of 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 approximately 1 μM to approximately 100 μM.

[0109] In some embodiments, intracellular calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 integers or non-integers within the aforementioned ranges.

[0110] In some embodiments, intracellular calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 integers or non-integers 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 viral particles called virions attach to and enter the host's susceptible cells. Calcium signaling regulates the entry, production, and transmission of viruses within host cells, thereby allowing viral diseases to spread. For example, host cell calcium signaling is triggered by the activation of STIM1-mediated and Orai-mediated calcium influx, which allows the virus to further budding and multiply within the host cell.

[0113] Viral diseases are diverse and classified according to structural characteristics such as genome type, virion shape, and replication site. In some, unspecified examples, viral diseases include hemorrhagic fever viruses. In some aspects, hemorrhagic fever viruses are arenaviruses, filoviruses, bunyaviruses, flaviviruses, rhabdoviruses, or combinations thereof. Unspecified 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, and Rift Valley virus.

[0114] This specification discloses compositions and methods for the prophylactic amelioration of viral diseases and their symptoms, such as by administration of a calcium channel inhibitor such as a CRAC inhibitor. In some embodiments, methods of ameliorating the symptoms of a viral disease in a human are shown. In some embodiments, a method of ameliorating the symptoms of a viral disease in a human is disclosed, the method comprising identifying a human who requires prophylactic amelioration of the symptoms of a viral disease, and administering an intracellular calcium signaling inhibitor to the human at a dosage sufficient to prophylactically ameliorate said symptoms.

[0115] In some embodiments, common symptoms of viral diseases include fever or hemorrhagic diathesis. In further embodiments, the symptoms of a viral disease include facial flushing, chest flushing, petechiae, capillary leakage, hemorrhage, swelling, edema, hypotension, shock, or combinations thereof. In further embodiments, the symptoms of a viral disease include malaise, myalgia, headache, vomiting, diarrhea, or combinations 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, amelioration of the symptoms of a viral disease further comprises administering an antiviral agent or a vaccine.

[0117] In some embodiments, the intracellular calcium signaling inhibitor is delivered to achieve a tissue level concentration equal to, near, or exceeding the in vitro IC 50 value determined for the compound. In some embodiments, the intracellular calcium signaling inhibitor is the in vitro IC<s 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, It is delivered to achieve tissue-level concentrations of 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, intracellular calcium signaling inhibitors are determined to be effective in vitro against compounds. 50 The values ​​are delivered to achieve tissue-level concentrations that are 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, or non-integer values ​​within the aforementioned ranges.

[0119] In some embodiments, the intracellular calcium signaling inhibitor is available in concentrations of 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 2 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, It is delivered to achieve tissue-level concentrations of 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 approximately 1 μM to approximately 100 μM.

[0120] In some embodiments, intracellular calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 integers or non-integers within the aforementioned ranges.

[0121] In some embodiments, intracellular calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 integers or non-integers within the aforementioned ranges.

[0122] In some embodiments, the method includes a step of prophylactically improving the symptoms of an acute viral disease. In some embodiments, the method includes a step of prophylactically improving the symptoms of a chronic viral disease.

[0123] A step to preventively improve symptoms of a viral disease includes a step to reduce the severity, likelihood of onset, or duration of at least one symptom of the viral disease. A step to preventively improve symptoms of a viral disease includes a step to reduce the severity, likelihood of onset, or duration of at least one symptom of the viral disease to a point where the at least one symptom does not occur in a person. In some embodiments, a step to preventively improve symptoms of a viral disease includes a step to reduce the severity, likelihood of onset, or duration of 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 symptoms of a viral disease, including a step to reduce 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 disorders> T helper cells (Th cells) are crucial for immune system function. Th cells regulate the immune system by releasing T cell cytokines, including chemokines, interferons, interleukins, lymphokines, tumor necrosis factor, or combinations thereof. T helper 17 cells (Th17) are a subset of pro-inflammatory Th cells, defined by their production of interleukin 17 (IL-17). Dysregulation of Th17 cells is associated with inflammatory and autoimmune diseases. Calcium signaling plays a significant role in regulating Th17 differentiation.

[0125] This specification discloses compositions and methods for the prophylactic improvement of Th17-induced diseases and their symptoms, including the administration of calcium channel inhibitors such as CRAC inhibitors. In some embodiments, methods for improving the symptoms of Th17-induced diseases in humans are disclosed. In some embodiments, methods for improving the symptoms of Th17-induced diseases in humans are disclosed, the methods comprising the steps of identifying a person in need of prophylactic improvement of the symptoms of a Th17-induced disease, 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. Inflammatory symptoms in a person include local redness, swelling, heat, pain, stiffness, fever, chills, fatigue, headache, loss of appetite, or a combination thereof. In some embodiments, the symptoms occur on the body of a person, including the torso, arms, hands, fingers, legs, feet, toes, head, neck, bones, joints, throat, nasal cavity, eyes, or a combination thereof.

[0127] In other embodiments, Th17-induced diseases include chronic inflammation or chronic inflammatory diseases. Chronic inflammatory diseases include, but are not limited to, hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, or cancer.

[0128] In further embodiments, Th17-induced diseases include autoimmune diseases. Autoimmune diseases are diseases in which the body's immune system attacks normal cells. Autoimmune diseases occur in the heart, kidneys, liver, lungs, skin, endocrine glands, exocrine glands, digestive system, tissues, blood, nervous system, or vascular system. Examples of autoimmune diseases that are not limited to these include rheumatoid arthritis, lupus, celiac disease, psoriasis, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes mellitus, alopecia areata, vasculitis, and temporal arteritis.

[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, improvement of symptoms of Th17-induced disease further comprises the step of administering an anti-inflammatory agent.

[0130] In some embodiments, intracellular calcium signaling inhibitors are determined to be effective in vitro against compounds. 50 It is delivered to achieve tissue-level concentrations equal to, near, or exceeding the value. In some embodiments, intracellular calcium signaling inhibitors are used to determine the in vitro IC25 of 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, It is delivered to achieve tissue-level concentrations of 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, intracellular calcium signaling inhibitors are determined to be effective in vitro against compounds. 50 The values ​​are delivered to achieve tissue-level concentrations that are 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, or non-integer values ​​within the aforementioned ranges.

[0132] In some embodiments, the intracellular calcium signaling inhibitor is available in concentrations of 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 2 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, It is delivered to achieve tissue-level concentrations of 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 approximately 1 μM to approximately 100 μM.

[0133] In some embodiments, intracellular calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 integers or non-integers within the aforementioned ranges.

[0134] In some embodiments, intracellular calcium signaling inhibitors are delivered to achieve tissue-level concentrations 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 integers or non-integers within the aforementioned ranges.

[0135] In some embodiments, the method includes a step of prophylactically improving the symptoms of an acute Th17-induced disease. In some embodiments, the method includes a step of prophylactically improving the symptoms of a chronic Th17-induced disease.

[0136] A step to preventively improve symptoms of Th17-induced disease includes reducing the severity, likelihood of onset, or duration of at least one symptom of Th17-induced disease. A step to preventively improve symptoms of Th17-induced disease includes reducing the severity, likelihood of onset, or duration of at least one symptom of Th17-induced disease to a point where the at least one symptom does not occur in a person. In some embodiments, a step to preventively improve symptoms of 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 Th17-induced disease, including reducing the severity, likelihood of onset, or duration of all symptoms of Th17-induced disease in a person, such as the symptoms of Th17-induced disease disclosed herein. In some embodiments, the subject is a non-human mammal rather than a human.

[0137] <Specific terms> Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they are generally understood to be in relation to the claimed subject matter. If there are multiple definitions of a term herein, the definition in this section shall prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referenced herein are incorporated by reference. Where URLs or other such identifiers or addresses are referenced, it is understood that such identifiers may change and certain information on the Internet may appear or disappear, but equivalent information can be found through an Internet search. References to such information are evidence of its availability and public dissemination.

[0138] It is understood that the general statements above and the detailed statements below are typical and illustrative only and do not limit the subject matter claimed. In this application, the use of the singular form includes the plural form unless otherwise specified. It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include multiple referents unless otherwise explicitly indicated. In this application, the use of "or" means "and / or" unless otherwise specified. Furthermore, the use of the term "including" is not limited to the other forms such as "include," "includes," and "included."

[0139] Section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described herein.

[0140] Standard definitions of chemical terms, though not limited to them, can be found in references, including 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 spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology may be used.

[0141] Unless otherwise specified, the nomenclature, testing methods, testing techniques, analytical chemistry, organic synthesis chemistry, medicinal chemistry, and medicinal chemistry described herein and used in connection therewith are recognized in the art. 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 manufacturer's specification kits, or as commonly performed in such techniques or as described herein. The aforementioned techniques and procedures may generally be performed in the conventional way and as described in various general and more specific references cited and discussed throughout this specification.

[0142] It should be understood that the methods and compositions described herein are not limited to the specific methodologies, protocols, cell lines, constructs, and reagents described herein, and that such may vary. It should also be understood that the terms used herein are for the purpose of describing only specific embodiments and are not intended to limit the scope of the methods, compounds, and compositions described herein.

[0143] The terms "kit" and "product" are used as synonyms.

[0144] The terms “subject” or “patient” encompass both mammals and non-mammals. Examples of mammals include, but are not limited to, members of the following mammalian classifications: humans, non-human primates such as chimpanzees, and other apes and monkeys; domesticated animals such as cattle, horses, sheep, goats, and pigs; domesticated 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, preventively and / or therapeutically reducing, reducing, or improving the symptoms of a disease or illness; preventing further symptoms; improving or preventing the underlying cause of symptoms; inhibiting a disease or illness, for example, halting the progression of a disease or illness; alleviating a disease or illness; regressing a disease or illness; alleviating a condition caused by a disease or illness; or stopping a disease or illness. As used herein, the term “target protein” refers to a protein or a portion of a protein that can be bound to or interact with a compound described herein, such as a compound having a structure from the group of compounds A. 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 proteins” include, but are not limited to, mammalian STIM-1s such as human and rodent (e.g., mouse) STIM-1, D-STIM of Drosophila melanogaster, C-STIM of the nematode (C. elegans), and STIM of Anopheles gambia, and mammalian STIM-2s such as human and rodent (e.g., mouse) STIM-2. (See paragraphs

[0211] to

[0270] of US2007 / 0031814 and Table 3, which are incorporated herein by reference.) As described herein, such proteins are identified as those that are involved in, participate in, and / or provide, the influx or regulation of store-sensitive calcium, cytoplasmic calcium buffering, and / or the regulation of calcium levels in intracellular calcium stores (e.g., endoplasmic reticulum) or the movement of calcium in or out of intracellular calcium stores.

[0147] As used herein, “Orai protein” includes Orai1 (SEQ ID NO:1 as described in WO 07 / 081804), Orai2 (SEQ ID NO:2 as described in WO 07 / 081804), or Orai3 (SEQ ID NO:3 as 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, or Orai3 (see Table I in WO 07 / 081804). As described herein, such proteins are identified as those that are involved in, participate in, and / or provide, the influx or regulation of store-sensitive calcium, cytoplasmic calcium buffering, and / or the regulation of calcium levels in intracellular calcium stores (e.g., endoplasmic reticulum) or the movement of calcium in, out of, or to intracellular calcium stores.

[0148] When referring to proteins (e.g., STIM, Orai), the terms “fragment” or “derivative” mean a protein or polypeptide that essentially conserves the same biological function or activity as the native protein in at least one assay. For example, a fragment or derivative of a referenced protein retains 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, “improvement” of symptoms of a particular disease, disorder, or illness by administration of a particular compound or pharmaceutical composition means a reduction in severity, delay in onset, slowing of progression, or reduction in duration, whether permanent or temporary, permanent or instantaneous, resulting from or in connection with the administration of the compound or composition.

[0150] The term “modulate” as used herein means interacting with a target protein, directly or indirectly, in such a way as to alter the activity of the target protein, including, but not limited to, or reducing the activity of the target protein.

[0151] As used herein, the term “modulator” refers to a compound that alters the activity of a target. For example, a modulator may cause an increase or decrease in the magnitude of a particular activity of a target compared to the magnitude of activity in the absence of the modulator. In certain embodiments, the modulator is an inhibitor that reduces the magnitude of one or more activities of a target. In certain embodiments, the inhibitor completely prevents one or more activities of a target.

[0152] As used herein, “modulation” of intracellular calcium means, but is not limited to, alterations or adjustments of intracellular calcium, including changes in calcium concentration in the cytoplasm and / or intracellular calcium storage organelles, such as the endoplasmic reticulum, and alterations in the dynamics of calcium flow into, out of, and within the cell. In some 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. Specific typical target activities include, but are not limited to, binding affinity, signaling, enzyme activity, tumor growth, inflammation or inflammation-related processes, and improvement of one or more symptoms associated with a disease or illness.

[0154] As used herein, the terms “inhibits,” “inhibiting,” or “inhibitor” of SOC channel activity or CRAC channel activity refer to the inhibition of store-sensitive calcium channel activity or calcium-release-dependent calcium channel activity.

[0155] As used herein, the term “acceptable” in reference to a formulation, composition, or component means that there is no persistent adverse effect on the health 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 inhibit the biological activity or properties of a compound and is relatively non-toxic; that is, the substance can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

[0157] As used herein, the term “pharmaceutical composition” means a product resulting from a mixture or combination of one or more active ingredients, and including both immobilized and unimmobilized combinations of active ingredients. The term “immobilized combination” means that one active ingredient, for example a compound having a structure from the group of compound A, and an adjuvant are administered to a patient simultaneously, together or sequentially, as separate entities, without any particular interfering time limit, where such administration provides the patient’s body with effective levels of two compounds. The latter also applies to cocktail therapies, for example, 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 group of Compound A described herein and other chemical components such as carriers, stabilizers, excipients, surfactants, dispersants, suspending agents, thickeners, and / or additives. Pharmaceutical compositions facilitate the administration of compounds to living organisms. Multiple techniques for administering compounds exist in the art, but are not limited to: intravenous, oral, aerosol, parenteral, ocular, subcutaneous, intramuscular, pulmonary, and topical administration.

[0159] As used herein, the terms “effective amount” or “therapeutically effective amount” refer to a sufficient amount of an administered drug or compound that alleviates, to some extent, one or more symptoms of the disease or illness being treated. As a result, the signs, symptoms, or causes of the disease may be reduced and / or mitigated, or other desirable changes to the biological system may be brought about. For example, an “effective amount” for therapeutic use is the amount of a composition containing a compound having a structure from group A of compounds that is required to provide a clinically significant reduction in disease symptoms. The appropriate “effective” amount in individual cases may be determined using techniques such as dose escalation studies.

[0160] As used herein, the terms “enhance” or “enhancing” mean increasing or extending a desired outcome in either efficacy or duration. Therefore, with respect to enhancing the effect of a therapeutic agent, the term “enhance” refers to the ability to increase or extend the effect of another therapeutic agent on a system in either efficacy or duration. As used herein, “enhancing effective amount” refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0161] As used herein, terms such as “concurrent administration” are intended to encompass the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered via the same or different routes of administration or at the same or different times of administration.

[0162] As used herein, the term “carrier” refers to a relatively non-toxic chemical compound or agent that facilitates the uptake of a compound into a cell or tissue.

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

[0164] The “metabolites” of the compounds disclosed herein are derivatives of the compound formed during its metabolism. 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 altered by an organism (including, but not limited to, hydrolysis and enzyme-catalyzed reactions). Enzymes can thus bring about specific structural changes in a compound. For example, cytochrome P450 catalyzes a variety of 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 may be identified by administration of the compounds to a host and analysis of tissue samples from the host, or by in vitro incubation of the compounds using hepatocytes and analysis of the resulting compounds.

[0165] "Bioavailability" refers to the percentage by weight of a compound disclosed herein (e.g., a compound from group A) that circulates and is delivered throughout the body of the animal or human being being tested. The total exposure (AUC(0-∞)) of a drug when administered intravenously is typically defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which a compound disclosed herein circulates and is absorbed throughout the body when a pharmaceutical composition is taken orally, compared to intravenous injection.

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

[0167] As used herein, “calcium homeostasis” refers to the maintenance of an overall balance of intracellular calcium levels and movement, including calcium signaling. As used herein, “intracellular calcium” refers to calcium located within a cell without specifying a particular cellular location. In contrast, “cytosolic” or “cytoplasmic” in relation to calcium refers to calcium located in the cytoplasm of a cell.

[0168] As used herein, effects on intracellular calcium are, but are not limited, alterations of the characteristics of intracellular calcium, including changes in the level of intracellular calcium and changes in the location and movement of calcium in, out of, or within cells or intracellular calcium stores or organelles. For example, effects on intracellular calcium may be alterations of properties such as the dynamics, sensitivity, rate, amplitude, and electrophysiological characteristics of calcium flow or movement occurring in a cell or a part thereof. Effects on intracellular calcium may also be alterations of intracellular calcium regulatory processes, including store-sensitive calcium influx, cytosolic calcium buffering, and changes in calcium levels in or to intracellular calcium stores or the movement of calcium out of or within them. Any of these characteristics can be assessed in a variety of ways, but are not limited, including assessment of calcium or other ion (particularly cation) levels, movement of calcium or other ion (particularly cation), fluctuations in calcium or other ion (particularly cation) levels, dynamics of calcium or other ion (particularly cation) flow, and / or transport of calcium or other ion (particularly cation) across membranes. The alterations may be such statistically significant changes. Therefore, for example, if intracellular calcium levels are said to differ between test cells and control cells, such a difference may be statistically significant.

[0169] As used herein, "involved in" with respect to the relationship between a protein and an aspect of intracellular calcium or intracellular calcium regulation means that when the expression or activity of a protein in a cell is reduced, altered, or removed, one or more aspects of intracellular calcium or intracellular calcium regulation are reduced, altered, or removed together or in association with it. Such alteration or reduction of expression or activity may result from alteration of the expression of the gene encoding the protein by altering the level of the protein. For example, a protein involved in an aspect of intracellular calcium, such as store-sensitive calcium influx, may therefore be a protein that provides or is involved in an aspect of intracellular calcium or intracellular calcium regulation. For example, a protein that provides store-sensitive calcium influx may be a STIM protein and / or an Orai protein.

[0170] As used herein, the proteins that are components of calcium channels are proteins involved in the multiprotein complex that forms the channel.

[0171] As used herein, “basal” or “quiescent” in relation to cytosolic calcium levels refers to the concentration of calcium in the cytoplasm of a cell that is not subjected to any condition resulting in the movement of calcium into, out of, or within the cell, such as an unstimulated cell. Basal or quiescent cytosolic calcium levels may be the concentration of free calcium (i.e., calcium not bound to the cell’s calcium-binding substance) in the cytoplasm of a cell that is not subjected to any condition resulting in the movement of calcium into or out of the cell, such as an unstimulated cell.

[0172] As used herein, "movement" with respect to ions, including cations such as calcium, refers to the movement or rearrangement (e.g., flow) of ions into, out of, or within cells. Therefore, ion movement includes, for example, movement from extracellular medium to cells, from inside cells to extracellular medium, from intracellular organelles or storage sites to cytosol, from cytosol to intracellular organelles or storage sites, from one intracellular organelle or storage site to another, and from extracellular medium to intracellular organelles or storage sites. This can involve the movement of ions from intracellular organelles or storage sites to extracellular culture media, 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 intracellular organelle or storage site. Therefore, cation entry may, for example, be the movement of cations from an extracellular medium or from an intracellular organelle or storage site into the cytoplasm of a cell, or the movement of cations from the cytoplasm or extracellular medium into an intracellular organelle or storage site. The movement of calcium from an intracellular organelle or storage site into the cytoplasm is also called “calcium release” from an intracellular organelle or storage site.

[0174] As used herein, “intracellular calcium-regulating proteins” refers to cellular proteins involved in the regulation, control, and / or modification of intracellular calcium. For example, such proteins may be involved in the modification or regulation of intracellular calcium in a variety of ways, including, but not limited to, involvement in cellular responses to signals transmitted within the cell via mechanisms including maintaining quiescent or basal levels of cytoplasmic calcium, or deviation of intracellular calcium from a quiescent or basal state. In relation to “intracellular calcium-regulating proteins,” “cellular” proteins are proteins associated with cells, such as cytoplasmic proteins, cell membrane-associated proteins, or intracellular membrane proteins. Intracellular calcium-regulating proteins 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 reduce, prevent, alleviate, and / or decrease the effects of a disease, symptom, or illness, resulting in an improvement of the disease or illness or at least a partial reduction of symptoms associated with the disease or illness, including a complete reduction such that the effects are zero or effectively zero.

[0176] As used herein, “cellular response” refers to a cellular response resulting from the movement of ions into, out of, or within a cell. Cellular responses may be related at least in part to ion-dependent cellular activities, such as calcium. Such activities may include, for example, cell activation, gene expression, endocytosis, exocytosis, cell transport, and apoptotic cell death.

[0177] As used herein, “immune cells” includes, but is not limited to, cells of the immune system and cells that perform functions or activity in immune responses, such as T cells, B cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, leukocytes, antigen-presenting cells, and natural killer cells.

[0178] As used herein, “cytokines” refers to small soluble proteins secreted by a secretory cell or by a cell that can alter the behavior or properties of another cell. Cytokines bind to cytokine receptors and cause intracellular behavior or properties, such as cell proliferation, death, or differentiation. Typical 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, erytropoietin, leukemia inhibitor (LIF), interferon, B7.1 (also known as CD80), B7.2 (also known as B70, CD86), TNF family members (TNF-α, TNF-β, LT-β, ​​CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail), and MIF.

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

[0180] "Selective inhibitors 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] "Selective inhibitor of CRAC channel activity" means 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 [something].

[0183] Preferred embodiments of the present invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided for illustrative purposes only. Many modifications, changes, and substitutions can be conceived by those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in the practice of the present invention. The following claims define the scope of the present invention, and methods and structures within the scope of these claims, as well as their equivalents, are intended to be encompassed thereby. [Examples]

[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 (taurolisocholic acid 3-sulfate) in or without GSK-7975A. Cells were contacted with propidium iodide and analyzed for cytonecrosis. TLCS treatment of individual cells in vitro mimics the effects of gallstones or other blockages in pancreatic juice secretion in vivo.

[0185] As shown in Figure 1A, TLCS induced necrosis in approximately 45% of cells during the experimental period. The addition of 10 μM GSK-7975A reduced this percentage of necrosis to approximately 23%. Asterisks indicate statistically significant changes. Cells not treated with TLCS exhibited approximately 10% necrosis. This result demonstrates that GSK-7975A reduces the necrotic effect of TLCS on mouse PACs.

[0186] Human PAC was extracted and incubated with a carrier (control) or natural bile acid TLCS in the presence or absence of GSK-7975A. Cells were contacted with propidium iodide and analyzed for cell death. Treatment of individual cells in vitro with TLCS mimics the effects of gallstones or other obstructions in pancreatic juice secretion in vivo.

[0187] As shown in Figure 1B, TLCS induced necrosis in approximately 45% of the cells among the experimental institutions. The 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 necrosis-inducing effect of TLCS on human PAC.

[0188] Example 2: The CRAC channel inhibitor (GSK-7975A) blocks histopathological changes in a mouse model of AP To evaluate the effect of the CRAC inhibitor on the histopathological progression of the pancreas, a mouse model of acute pancreatitis was used. Cerulein was used to overstimulate the CCK receptor in the standard calcium signaling pathway in the mouse pancreas. TLCS was used to induce acute pancreatitis by simulating an excess of bile acids, as experienced in gallstone-induced acute pancreatitis. Fatty acid ethyl ester (FAEE) was used to simulate alcohol-induced acute pancreatitis. Mice were treated with the acute pancreatitis reagent (cerulein (Figure 2A), TLCS (Figure 2B), or FAEE (Figure 2C)) alone or with the CRAC inhibitor at 10x or 40x of its IC 50 with the CRAC inhibitor GSK-7975A.

[0189] It has been observed that GSK-7975A significantly reduces the total histopathological score of the treated mice compared to mice treated with the reagent without the CRAC inhibitor. This effect is statistically significant and is more pronounced at 40x IC 50 than at 10x IC 50It was substantially more pronounced, but observed at lower concentrations. An asterisk indicates a statistically significant change. Its in vitro IC 50 GSK-7975A at doses that achieve tissue levels exceeding 10 or 40 times the value results in a significant decrease in the histopathological diagnosis of the pancreas.

[0190] The results shown in Figures 2A, 2B, and 2C demonstrate that CRAC inhibitors can improve the histopathological presentation of acute pancreatitis. This effect is observed independently of the inducing agent or the type of acute pancreatitis being modeled.

[0191] Example 3: Compound I and GSK-7975A inhibit CRAC channels. Compounds 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 had an average IC50 of 119 nM. 50 Orai1 / STIM1 channel, and an average IC of 895nM 50 It was determined that the Orai2 / STIM1 channel was inhibited. As shown in Figure 3B, the GSK-7975A produced an average IC of 398 nM. 50 Orai1 / STIM1 channel, and an average IC of 1453nM 50 It was determined that the Orai2 / STIM1 channel was inhibited. Compound I was approximately four times more potent against Orai1-type CRAC channels compared to GSK-7975A. Both compounds were more potent against Orai1 than against Orai2-type CRAC channels.

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

[0193] Example 4: Compound I stored sensitive Ca in mouse pancreatic acinar cells. 2+ Block incoming traffic (SOCE) Mouse PACs were isolated and analyzed for the effects of CRAC inhibitors on calcium reuptake into the ER. Cells were treated with cyclopiazonic acid (CPA) alone (Figure 4A) or in combination with CRAC inhibitor compound I (Figure 4B) to activate CRAC channels and Ca 2+ The cells were then released. Fifteen minutes after calcium release, excess calcium was provided to the cells, and calcium uptake into the ER was monitored. It was observed that cells treated with a CRAC inhibitor did not demonstrate calcium reuptake.

[0194] These results suggest that CRAC inhibitors may 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 either CRAC inhibitor compound I (Figure 5A) or GSK-7975A (Figure 5B), and their rates of calcium uptake were monitored. Both CRAC inhibitors reduced the rate of store-sensitive calcium inflow into the ER compared to 50% of the control level after treatment with 700 nM of the inhibitor. Compound I blocked 100% of reuptake at 10 mM.

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

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

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

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

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

[0201] Example 8: Compound I shows a strong effect in a calcineurin model of acute pancreatitis in mice. Mice were prophylactically treated with a CRAC inhibitor or vehicle, and then challenged with CCK to induce acute pancreatitis. Prophylactic intraperitoneal (ip) administration of compound I resulted in a significant and dose-dependent reduction of 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 in a dose-dependent manner. 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 result in Figure 8A above.

[0202] These results indicate that CRAC administration, prior to or in conjunction with a second drug suspected of causing or increasing the risk of acute pancreatitis, may provide prophylactic protection from or reduce the risk of acute pancreatitis.

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

[0204] CRAC inhibitor compound I acted similarly to or better than the positive control CsA at a maximum concentration of 20 mg / kg. Compound I resulted in a significant and dose-dependent decrease in cerulein-induced serum amylase and serum lipase activity.

[0205] Example 10: Compound I reduces pancreatic pathology in a therapeutic mouse model of cerulein. Seven intraperitoneal injections of cerulein were administered hourly to induce pancreatitis, and the animals were sacrificed eight hours after the first injection. Compound I was administered intraperitoneally 30 minutes before the first cerulein 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 measured in relation to observations of acinar cell degeneration, coagulation necrosis, and inflammation, as well as edema measurements. Compound I, when administered after the third cerulein injection, resulted in a significant 35% reduction in cerulein-induced conditions in the pancreas, which was consistent with the effect in the therapeutic mode. Prophylactic treatment with compound I also reduced the condition by 26%.

[0207] The results indicate that CRAC inhibitors, such as compound I, have a significant effect on pancreatic histopathological scores when administered prophylactically or therapeutically.

[0208] Example 11: Compound I caused TLCS-induced Ca in mouse pancreatic acinar cells. 2+ Block inflow. Mouse PACs were treated with 500 μM TLCS and 0.1 μM or 3 μM CRAC inhibitor compound I. Cytosolic calcium levels (measured as F345 / F380 ratio) were measured for each treatment. TLCS was used to reduce Ca from intracellular stores (not shown). 2+ It releases and initiates SOCE. In this experiment, 1 μM or 3 μM of compound I induces TLCS-induced Ca 2+ The inflow was completely blocked. The results are shown in Figure 11.

[0209] These results suggest that CRAC inhibitors may be effective in positively influencing 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 PACs involves ER calcium-dependent and CRAC / cytosolic calcium-dependent components. The calcium-dependent component is blocked by the introduction of the divalent cation chelating agent EGTA. Mouse acinar cells were treated with TLCS and either a vehicle, EGTA, or a CRAC inhibitor such as compound I, GSK-7975A, or compound II, and monitored for amylase release. It was observed that CRAC inhibitors mimicked EGTA in their effects on amylase release. See Figure 12.

[0211] These results indicate 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. CRAC inhibitor compound I inhibited TLCS-induced necrosis in mouse PACs.

[0213] These data, Ca 2+ Along with the amylase data, this shows 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 trial is to investigate the safety, tolerance, pharmacokinetics (PK), disease progression (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 associated SIRS.

[0215] Patients: The trial will enroll 30 patients at high risk of progression of moderate or severe pancreatitis who were assessed with an SIRS score of 2 or higher at trial entry.

[0216] standard: Inclusion criteria: All subjects must use acceptable contraception to ensure they are not pregnant during the trial and for at least 12 weeks after administration for males and 32 weeks after administration for females. In addition to the weight range of 55-95kg, the 18.5-35kg / m 2 Obesity index within the specified range. • The subject must be able to give informed consent and comply with the examination requirements and timetable; • Male and female subjects aged 18 or older are eligible. • The subject must be experiencing acute pancreatitis for the first time in their lifetime. The diagnosis of acute pancreatitis must be based on two of the following three criteria: (1) typical upper abdominal 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 image demonstrating changes in acute pancreatitis. • Subjects must demonstrate a medical history supporting an alcoholic, hypertriglyceridemia, or biliary etiology for the current onset of pancreatitis (for cholangiopancreatitis, ultrasound imaging must exclude stone obstruction during screening for the test). • Subjects must demonstrate a BISAP score of 3 or higher. • The trial treatment can be initiated within 48 hours of the onset of symptoms.

[0217] Exclusion criteria: • High probability of invasive endoductal intervention (e.g., ERCP) the following week. • Recurrence of pancreatitis. • CT evidence of pancreatic necrosis at trial entry. · Severe chronic renal insufficiency (diet modification in kidney disease, with a prescription of 30 mL / min or dependent on renal dialysis). · New York Heart Association class II or higher heart failure. · Oxygen-dependent chronic obstructive pulmonary disease (COPD). · Liver cirrhosis. · Severe anemia (hemoglobin less than 8 g / dL). · Hematocrit less than 35% or greater than 45% at the time of entry into the study (fluids may be administered to correct hematocrit prior to randomization, provided that the study treatment is initiated within 48 hours of symptom onset). · Serum alanine aminotransferase greater than 250 IU / L at the time of entry into the study. · Clinical suspicion of ascending cholangitis at the time of entry into the study. · Active gastrointestinal bleeding. · Current malignancy (other than basal cell carcinoma of the skin) not in remission. · Changes in mental status. · Current lactation or pregnancy. · Women of childbearing potential who are not willing to use adequate and effective contraception (less than 2 years postmenopausal or not surgically sterilized). · Known hypersensitivity to the components of the investigational drug. · Dependent relationship with the investigator or sponsor. · Participation in a study of the investigational drug during the current clinical trial or within 30 days prior to the start of the current clinical trial.

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

[0219] The study enrolls 45 high-risk patients with moderate or severe pancreatitis, who are evaluated with two or more SIRS scores at the time of entry into the study.

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

[0221] In clinical trials, administration of the substance will be initiated within 24 hours of the onset of acute pancreatic symptoms or within 18 hours of hospitalization. Subjects will be randomized in a 1:1 ratio to receive either a CRAC inhibitor or a 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 is 14 days and consists of a screening assessment, part of a minimum 7-day in-hospital observation period, followed by a double-blind treatment period of up to 7 days, and a final follow-up visit on day 14.

[0223] Primary evaluation criteria: • Serum concentration of C-reactive protein. • Changes in SIRS over 48 hours. • Levels of blood amylase and lipase.

[0224] Secondary endpoints: CRAC inhibitors vs. placebo: • Safety of CRAC inhibitors in this patient population based on routine safety clinical testing. • Physical examination and monitoring of vital signs, ECG, and reporting of adverse events. • Effects of CRAC inhibitors on other plasma inflammatory markers (interleukin-6, matrix metalloproteinase-9, tumor necrosis factor alpha, etc.). • Effects of CRAC inhibitors on the clinical course of pancreatitis (based on changes in clinical rating scales such as bedside index for acute pancreatitis severity (BISAP), systemic inflammatory response syndrome (SIRS), and acute-chronic physiological classification assessment II (APACHE II) scores, and contrast-enhanced abdominal computed tomography (CT)). • Progression of the Organ Failure Assessment (SOFA) score over time • Progression of the Multiple Organ Failure Score (MODS) • Progression of systemic inflammatory response syndrome • Progression of inflammatory and anti-inflammatory mediators (IL-1RA, IL-10, IL-6, IL-18, TNF-α, ICAM-1, IL-10, etc.). • Increased attention to high dependence or length of stay in the intensive care unit and hospitalization.

[0225] Example 15: Compound I inhibits the budding of Junin virus in infected VeroE6 cells. VeroE6 cells infected with attenuated live 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, and 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 decrease in JUNV virus production after treatment with compound I.

[0226] These data, Ca 2+ The data, along with the results, demonstrates that compound I is effective in inhibiting viral budding of the JUNV virus.

[0227] Example 16: Compound I is a store-sensitive Ca 2+ It specifically inhibits the influx-dependent differentiation of Th1, Th2, and Th17 cells. Naive, stimulated mouse T cells cultured under Th1, Th2, and Th17 polarization conditions were treated with inhibitor compound I of DMSO, DMSO + 500 μM TLCS, or DMSO + 500 μM TLCS + 1 μM CRAC. Store-sensitive Ca 2+SOCE inflow (SOCE) was quantified at each treatment stage. Compound I blocked SOCE more strongly in differentiated Th17 cells than in naive, Th1, or Th2 cells. Furthermore, IL-17A production by Th17 cells was more severely affected in the presence of compound I compared to IFN-γ and IL-4 production by Th1 and Th2 cells, respectively.

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

Claims

1. Use of an intracellular calcium signaling inhibitor, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, in the manufacture of a pharmacopoeia for treating asparaginase-induced pancreatitis in a subject, Use comprising administering to the subject a therapeutically effective amount of the intracellular calcium signaling inhibitor or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

2. The use according to claim 1, wherein the asparaginase-induced pancreatitis is acute pancreatitis.

3. The use according to claim 1, further comprising improving the symptoms of asparaginase-induced pancreatitis.

4. The use according to claim 3, 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.

5. The use according to claim 3, wherein the symptoms are symptoms of severe acute pancreatitis.

6. The use according to claim 3, wherein the symptoms include at least one of pancreatic necrosis and damage to extrapancreatic organs.

7. The use according to claim 3, wherein the symptoms are symptoms of chronic pancreatitis.

8. The use according to claim 3, wherein the symptoms include at least one of persistent abdominal pain, digestive disorders, malabsorption of fats, pain during food intake, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP inflammatory marker, decreased bicarbonate production, elevated fecal elastase levels, elevated serum trypsinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels.

9. The use according to claim 3, wherein the symptoms include at least one of an elevated ESR level, an elevated IgG4 level, an increase in rheumatoid factor, the presence of ANA antibodies, and the presence of anti-smooth muscle antibodies.

10. The use according to claim 3, wherein the symptoms include steatorrhea, 7 grams or more of stool or fecal steatorrhea over 24 hours with 100 g of fatty food, and at least one of fecal elastase in a stool sample at a value of less than 200 μg / g.

11. The use according to claim 3, 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.

12. The use according to claim 3, wherein the symptoms include an increase in serum amylase concentration.

13. The use according to claim 3, wherein the symptoms include an increase in serum lipase concentration.

14. The use according to claim 3, wherein the symptoms include the discovery of necrosis by computed tomography (CT) scan.

15. The use according to claim 3, wherein the symptoms include premature activation of digestive enzymes.

16. The use according to claim 15, wherein the premature activation of digestive enzymes occurs in the pancreas of the subject.

17. The use according to claim 15, wherein the premature digestive enzyme activation includes an enzyme, the enzyme being trypsin.

18. The intracellular calcium signaling inhibitor is N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxyno[2,3-b]pyridine-6-yl)pyridine-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazole-2- The use according to claim 1, wherein the product is (yl)-1H-pyrazole-5-yl)pyrimidine-2-amine, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazole-4-yl)phenyl)benzamide, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazole-2-yl)-1H-pyrazole-4-yl)phenyl)isonicotinamide, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

19. The use according to claim 18, wherein the intracellular calcium signaling inhibitor is N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazine-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

20. The use according to claim 18, wherein the intracellular calcium signaling inhibitor is N-(5-(7-chloro-2,3-dihydro-[1,4]dioxyno[2,3-b]pyridine-6-yl)pyridine-2-yl)-2,6-difluorobenzamide, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

21. The use according to claim 18, wherein the intracellular calcium signaling inhibitor is N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazole-2-yl)-1H-pyrazole-5-yl)pyrimidine-2-amine, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

22. The use according to claim 18, wherein the intracellular calcium signaling inhibitor is 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazole-4-yl)phenyl)benzamide, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

23. The use according to claim 18, wherein the intracellular calcium signaling inhibitor is 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazole-2-yl)-1H-pyrazole-4-yl)phenyl) isonicotinamide, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

Images