Treatment of pancreatitis

Abstract

Disclosed herein are compositions and methods for improving pancreatitis through pharmacological manipulation of calcium signaling. Such compositions and methods can be used to improve symptoms of acute or chronic pancreatitis or to reduce the likelihood or severity of pancreatitis in individuals at risk for the condition. In other embodiments, disclosed herein are compositions and methods for improving viral disease through pharmacological manipulation of calcium signaling. In further embodiments, disclosed herein are compositions and methods for improving Thl7-induced disease through pharmacological manipulation of calcium signaling.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201680024735.5 (International Application No. PCT / US2016 / 019924) entitled “Treatment of Pancreatitis”, filed on February 26, 2016.

[0002] Cross-referencing

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 126,386, filed February 27, 2015, which is incorporated herein by reference in its entirety. Background Technology

[0004] Acute pancreatitis is the leading cause of gastrointestinal hospitalizations in the United States and represents a significant expense. In severe cases, acute pancreatitis exhibits a mortality rate of 10-25%, compared to an overall mortality rate of 3-5%. Currently, there are no disease-modifying therapies available for patients with this condition. Summary of the Invention

[0005] This document provides embodiments of methods relating to improving symptoms of pancreatitis in mammals such as humans. In other embodiments, this document describes methods for improving symptoms of viral infections in mammals such as humans. In further embodiments, this document describes methods for improving symptoms of T helper 17 cell (Th17)-induced inflammation and autoimmune diseases.

[0006] In some embodiments, the method includes the steps of: identifying a person who needs to improve symptoms of pancreatitis; and administering an intracellular calcium signaling inhibitor to the person at a dose sufficient to improve the symptoms. In other embodiments, the method includes the steps of: identifying a person who needs to improve symptoms of a viral disease; and administering an intracellular calcium signaling inhibitor to the person at a dose sufficient to improve the symptoms. In a further embodiment, the method includes the steps of: identifying a person who needs to improve symptoms of Th17-induced disease; and administering an intracellular calcium signaling inhibitor to the person at a dose sufficient to improve the symptoms. In some aspects, the intracellular calcium signaling inhibitor is a SOC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the STIM1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the Orai1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the Orai2 protein.

[0007] In some respects, the intracellular signaling inhibitor is a compound having the following structure: (collectively referred to as "Compound A"), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the intracellular calcium signaling inhibitor is a compound having a structure derived from Compound A or a nanoparticle formulation thereof, including a nanoparticle suspension or emulsion.

[0008] In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof. In some respects, this intracellular calcium signaling inhibitor is selected from the following compounds: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(4-(1-ethyl-3-(thiazolyl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl) -2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazol-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol- 5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1-methyl-1H-pyrazol-5-carboxamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxane-hexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluoro Benzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-Trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazo-2-yl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridine-2 -yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3] Dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide (collectively, “Compound A”), or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof. In some aspects, the symptoms are those of acute pancreatitis. In some aspects, the symptoms include at least one of the following: pancreatic inflammation and edema, upper abdominal pain radiating to the back, pain radiating to the left upper quadrant of the back, nausea, vomiting, vomiting that worsens with eating, increased heart rate, tachycardia, increased respiratory rate, increased blood pressure, decreased blood pressure, dehydration, abdominal tenderness, fever, chills, peritonitis, hemodynamic instability, and reflex paralytic ileus. In some aspects, the symptoms are those of severe acute pancreatitis. In some aspects, the symptoms include at least one of pancreatic necrosis and extrapancreatic organ injury. In some aspects, the symptoms are those of chronic pancreatitis. In some aspects, the symptoms include at least one of the following: persistent abdominal pain, digestive defects, malabsorption of fat, pain during food intake, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP inflammatory markers, impaired bicarbonate production, elevated fecal elastase levels, elevated serum trypsinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels. In some aspects, the symptoms include at least one of the following: elevated ESR levels, elevated IgG4 levels, elevated rheumatoid factor, presence of ANA antibodies, or presence of anti-smooth muscle antibodies, any one of which can indicate chronic pancreatitis in a person. In some aspects, the symptoms include at least one of the following: steatorrhea, Sudan chemical staining of stool, or excretion of 7 grams or more of fecal fat within 24 hours after a 100g fat diet; and a fecal elastase value of less than 200 μg / g in the stool sample. In some aspects, the symptoms include at least one of the following: abdominal pain, elevated blood amylase levels, elevated blood lipase levels, enlarged pancreas, nausea, vomiting, internal bleeding, paralytic ileus, fever, jaundice, weight loss, and elevated heart rate. In some aspects, the symptoms include elevated serum amylase levels. In some aspects, the symptoms include elevated serum lipase levels. In some aspects, the symptoms include necrosis detected by computed tomography (CT) scan. In some aspects, the symptoms include premature activation of a digestive enzyme. In some aspects, this premature activation of the digestive enzyme occurs in the pancreas of the person. In some aspects, the enzyme includes trypsin.

[0009] Some implementations relate to methods for preventing or improving symptoms associated with pancreatic disease in individuals at risk of pancreatic disease. In some implementations, the method includes the steps of: identifying individuals with risk factors associated with pancreatic disease; and administering an intracellular calcium signaling inhibitor at a dose sufficient to prevent or improve said side effects. In some aspects, the intracellular calcium inhibitor is a SOC channel inhibitor. In some aspects, the intracellular calcium inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium inhibitor is a compound having a structure from compound A of group A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects, the pancreatic disease includes symptoms of acute pancreatitis. In some aspects, the pancreatic disease includes symptoms of chronic pancreatitis. In some respects, the person has pancreatitis due to a regimen involving the administration of at least one of the following: steroids, such as corticosteroids, prednisolone, HIV drugs, inosine, pentamidine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogen, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, glipins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone, and olanzapine. In some respects, the person has been identified as carrying a genetic form of pancreatitis. In some respects, the person has a mutated allele of at least one of the following: trypsin 1 encoding trypsinogen, SPINK1 encoding a trypsin inhibitor, and a cystic fibrosis transmembrane transport regulator. In some respects, the person has pancreatitis due to at least one of the following: hypercalcemia, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic mitosis, congenital pancreatic malformation, type 2 diabetes, pancreatic cancer, pancreatic duct stones, vasculitis, pancreatic small vessel inflammation, coxsackievirus infection, and porphyria, such as acute intermittent porphyria and erythropoietic protoporphyria. In some respects, the person's health condition has been affected by at least one of the following: gallstones, alcohol poisoning, alcohol intoxication, trauma, mumps, autoimmune disease, scorpion sting, hyperlipidemia, hypothermia, hyperparathyroidism, endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid.In some respects, the physical health of the person in question has been affected by at least one of the following: Coxsackievirus, cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella bacteria, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungi, Ascaris parasites, Cryptosporidium cells, and Toxoplasma cells.

[0010] Some embodiments relate to methods for preventing or improving viral disease-related symptoms in persons at risk of viral disease. In some embodiments, the method includes the steps of: identifying persons with risk factors associated with viral disease; and administering an intracellular calcium signaling inhibitor at a dose sufficient to prevent or improve said side effects. Some embodiments relate to compositions for improving viral disease symptoms in persons, the improvement including the steps of: identifying persons requiring improvement of viral disease symptoms; and administering an intracellular calcium signaling inhibitor to said persons at a dose sufficient to improve said symptoms. In some aspects, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the STIM1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the Orai1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the Orai2 protein. In some aspects, the intracellular calcium signaling inhibitor is a compound having a structure from compound A of group A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof. In some aspects, the intracellular calcium signaling inhibitor blocks the budding of a viral disease. In some aspects, the viral disease is a hemorrhagic fever virus. In further aspects, the hemorrhagic fever virus is a sand-like virus, a fibrillin virus, a bunyavirus, a flavivirus, a rhabdovirus, or a combination thereof. In a further aspect, the hemorrhagic fever virus is Ebola virus, Marburg virus, Lassa virus, Junín virus, rotavirus, West Nile virus, Zika virus, Coxsackie virus, hepatitis B virus, Epstein-Barr virus, dengue virus, or Rift Valley virus. In some aspects, the symptoms are fever or hemorrhagic diathesis. In a further aspect, the symptoms of viral disease include at least one of the following: facial flushing, chest flushing, petechiae, capillary leakage, hemorrhage, swelling, edema, hypotension, shock, malaise, muscle pain, headache, vomiting, diarrhea, or a combination thereof.

[0011] Some embodiments relate to methods for preventing or improving symptoms associated with Th17-induced disease in individuals at risk of Th17-induced disease. In some embodiments, the method includes the steps of: identifying individuals with risk factors associated with Th17-induced disease; and administering an intracellular calcium signaling inhibitor at a dose sufficient to prevent or improve said side effects. Some embodiments relate to compositions for improving symptoms of Th17-induced disease in individuals, the improvement including the steps of: identifying individuals requiring improvement of pancreatitis symptoms; and administering an intracellular calcium signaling inhibitor to said individuals at a dose sufficient to improve said symptoms. In some aspects, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the STIM1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the Orai1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the Orai2 protein. In some aspects, the intracellular calcium signaling inhibitor is a compound having a structure from compound A of group A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof. In some aspects, the intracellular calcium signaling inhibitor blocks the differentiation of Th17 cells. In some aspects, the Th17-induced disease is a chronic inflammatory disease. In a further aspect, the chronic inflammatory disease is hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, or cancer. In other aspects, the Th17-induced disease is an autoimmune disease. In further aspects, the autoimmune disease includes rheumatoid arthritis, lupus, celiac disease, psoriasis, Sjorgen's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, or temporal arteritis. In some aspects, the symptoms of this Th17-induced disease include at least one of the following: localized redness, swelling, heat, pain, stiffness, fever, chills, fatigue, headache, or loss of appetite. In some aspects, the symptoms occur on the body, including the trunk, arms, hands, fingers, legs, feet, toes, head, neck, bones, joints, throat, sinuses, eyes, or combinations thereof.

[0012] Some embodiments relate to a composition comprising an intracellular calcium signaling inhibitor and at least one drug associated with a negative effect on pancreatic activity. In some aspects, the drug is selected from: steroids such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone and olanzapine, azathioprine, and valproic acid. In some aspects, the intracellular calcium signaling inhibitor is a SOC inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a CRAC inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a compound having a structure from compound A of group A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some respects, this intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In other respects, this intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0013] Some aspects relate to a dosing regimen that includes administering to an individual a drug associated with negative effects on pancreatic activity, and administering an intracellular calcium signaling inhibitor. In some aspects, the drug is selected from: steroids such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone and olanzapine, azathioprine, and valproic acid. In some aspects, the intracellular calcium signaling inhibitor is a SOC inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a CRAC inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a compound having a structure from compound A of group A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some respects, this intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0014] Some embodiments relate to compositions for improving symptoms of pancreatitis in humans, the improvement comprising the steps of: identifying a person in need of improvement of pancreatitis symptoms; and administering an intracellular calcium signaling inhibitor to the person at a dose sufficient to improve the symptoms. In some aspects, the intracellular calcium signaling inhibitor is a SOC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the STIM1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the Orai1 protein. In some aspects, the intracellular calcium signaling inhibitor inhibits a channel containing the Orai2 protein. In some aspects, the intracellular calcium signaling inhibitor is a compound having a structure from compound A of group A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof. In some aspects, the composition further comprises an analgesic. In some aspects, the analgesic comprises opioids. In some aspects, the analgesic comprises morphine. In some aspects, the symptoms are symptoms of acute pancreatitis. In some aspects, the symptoms include at least one of the following: pancreatic inflammation and edema, upper abdominal pain radiating to the back, pain radiating to the left upper quadrant of the back, nausea, vomiting, vomiting that worsens with eating, increased heart rate, tachycardia, increased respiratory rate, increased blood pressure, decreased blood pressure, dehydration, abdominal tenderness, fever, chills, peritonitis, hemodynamic instability, and reflex paralytic ileus. In some aspects, the symptoms are symptoms of severe pancreatitis. In some aspects, the symptoms include at least one of pancreatic necrosis and extrapancreatic organ injury. In some aspects, the symptoms are symptoms of chronic pancreatitis. In some aspects, the symptoms include at least one of the following: persistent abdominal pain, digestive defects, malabsorption of fat, pain during food intake, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP inflammatory markers, impaired bicarbonate production, elevated fecal elastase levels, elevated serum trypsinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels. In some respects, the symptoms include at least one of the following: elevated ESR levels, elevated IgG4 levels, elevated rheumatoid factor, presence of ANA antibodies, or presence of anti-smooth muscle antibodies, any one of which can indicate chronic pancreatitis in a person.In some aspects, the symptoms include at least one of the following: steatorrhea, Sudan chemical staining of stool, or excretion of 7 grams or more of fecal fat within 24 hours after a 100g fat diet, and a fecal elastase value of less than 200 μg / g in a stool sample. In some aspects, the symptoms include at least one of the following: abdominal pain, elevated blood amylase levels, elevated blood lipase levels, pancreatic enlargement, nausea, vomiting, internal bleeding, paralytic ileus, fever, jaundice, weight loss, and elevated heart rate. In some aspects, the symptoms include premature activation of digestive enzymes. In some aspects, this premature activation of digestive enzymes occurs in the pancreas of the person. In some aspects, the enzyme includes trypsin.

[0015] Some aspects relate to a composition for preventing or improving pancreatic disease-related symptoms in persons at risk of pancreatic disease, the prevention or improvement comprising the steps of: identifying persons with risk factors associated with pancreatic disease; and administering an intracellular calcium signaling inhibitor at a dose sufficient to prevent or improve said side effects. In some aspects, the intracellular calcium inhibitor is a SOC channel inhibitor. In some aspects, the intracellular calcium inhibitor is a CRAC channel inhibitor. In some aspects, the intracellular inhibitor is a compound having the structure of compound A from the group thereof, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug therefrom. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug. In some aspects, the pancreatic condition includes symptoms of acute pancreatitis. In some aspects, the pancreatic condition includes symptoms of chronic pancreatitis. In some aspects, the person undergoes a dosing regimen comprising administration of at least one of the following: steroids such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogen, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone, and olanzapine. In some respects, the person was identified as carrying a genetic form of pancreatitis. In some respects, the person carried a mutated allele of at least one of the following: trypsin 1 encoding trypsinogen, SPINK1 encoding a trypsin inhibitor, and a cystic fibrosis transmembrane transport regulator. In some respects, the person suffered from at least one of the following: hypercalcemia, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic mitosis, congenital pancreatic malformation, type 2 diabetes, pancreatic cancer, pancreatic duct stones, vasculitis, pancreatic small vessel inflammation, Coxsackie virus infection, and prophyra, such as acute intermittent porphyria and erythropoietic proporphyria. In some respects, the person's physical health has been affected by at least one of the following: gallstones, alcohol poisoning, alcohol poisoning, trauma, mumps, autoimmune diseases, scorpion stings, hyperlipidemia, hypothermia, hyperparathyroidism and endoscopic retrograde cholangiopancreatography, azathioprine and valproic acid.In some respects, the physical health of the person in question has been affected by at least one of the following: cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella bacteria, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungi, Ascaris parasites, Cryptosporidium cells, and Toxoplasma cells.

[0016] Incorporation

[0017] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually cited and incorporated herein by reference.

[0018] Specifically, PCT Publication No. WO 2011 / 139489A2, published on November 10, 2011, is incorporated herein by reference in its entirety; PCT Publication No. WO 2009 / 035818, published on March 19, 2009, is incorporated herein by reference in its entirety; PCT Publication No. WO 2010 / 025295, published on June 17, 2010, is incorporated herein by reference in its entirety; PCT Publication No. WO 2010 / 027875, published on June 10, 2010, is incorporated herein by reference in its entirety; PCT Publication No. WO 2011 / 034962, published on July 28, 2011, is incorporated herein by reference in its entirety; and PCT Publication No. WO 2011 / 034962, published on January 26, 2012, is incorporated herein by reference in its entirety. PCT Publication No. WO 2011 / 139489, published on March 8, 2012, is incorporated herein by reference in its entirety; PCT Publication No. WO 2011 / 139765, published on May 18, 2012, is incorporated herein by reference in its entirety; PCT Publication No. WO 2012 / 027710, published on May 18, 2012, is incorporated herein by reference in its entirety; PCT Publication No. WO 2012 / 170931, published on February 21, 2013, is incorporated herein by reference in its entirety; PCT Publication No. WO 2012 / 170951, published on April 25, 2013, is incorporated herein by reference in its entirety; PCT Publication No. WO 2013 / 0596 ...2 / 027710, published on May 18, 2012, is incorporated herein by reference in its entirety; PCT Publication No. WO 2012 / 027710, published on February 21, 2013, is incorporated herein by reference in its entirety; PCT Publication No. WO 2012 / 027710, published on April 25, 2013, is incorporated herein by reference in its entirety; PCT Publication No. WO 2012 / 027710, published on February 21, 2013, is incorporated herein by reference in its entirety; PCT Publication No. WO 2012 / 027710, published on April 25, PCT Publication No. 2013 / 059677 is incorporated herein by reference in its entirety; PCT Publication No. 2014 / 043715, published on 20 March 2014, is incorporated herein by reference in its entirety; and PCT Publication No. 2014 / 059333, published on 17 April 2014, is incorporated herein by reference in its entirety. Attached Figure Description

[0019] The novel features of the invention are specifically set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description of illustrative embodiments utilizing the principles of the invention, and the accompanying drawings, in which:

[0020] Figure 1A This shows necrosis of mouse acinar cells after treatment with TLCS.

[0021] Figure 1B This shows necrosis of human acinar cells after treatment with TLCS.

[0022] Figure 2A Histopathological score of Caelurin-induced acute pancreatitis.

[0023] Figure 2B The histopathological score of TLCS-induced acute pancreatitis is displayed.

[0024] Figure 2C The histopathological score of FAEE-induced acute pancreatitis is displayed.

[0025] Figure 3A The IC50 of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide (“Compound I”) is shown. 50 Measurement.

[0026] Figure 3B IC showing 2,6-difluoro-N-(1-(4-hydroxy-2-(trifluoromethyl)benzyl)-1H-pyrazol-3-yl)benzamide (“GSK-7975A”) 50 Measurement.

[0027] Figure 4A This shows calcium uptake in the absence of CRAC inhibitors.

[0028] Figure 4B This shows calcium uptake in the presence of CRAC inhibitors.

[0029] Figure 5A This shows calcium influx in the presence of CRAC inhibitor compound I.

[0030] Figure 5B This shows calcium influx in the presence of the CRAC inhibitor GSK-7975A.

[0031] Figure 6A This shows calcium influx in the absence of CRAC inhibitors.

[0032] Figure 6BThis shows the relative calcium influx in the presence of CRAC inhibitor compound I and GSK-7975A compared to the control.

[0033] Figure 7 This shows that compound I has an IC50 response relative to multiple cytokines. 50 value.

[0034] Figure 8A The histopathological scores of a range of concentrations of compound I are displayed.

[0035] Figure 8B This shows the concentration of compound I in the pancreas as a function of dosage.

[0036] Figure 9A Serum amylase levels were shown in mice without induced (normal) and mice induced with acute pancreatitis, in the presence and absence of CRAC inhibitors.

[0037] Figure 9B Serum lipase levels were shown in mice without induced (normal) and mice induced with acute pancreatitis, in the presence and absence of CRAC inhibitors.

[0038] Figure 10 Histopathological scores of mice treated with therapeutic and prophylactic methods following acute pancreatitis induction are shown.

[0039] Figure 11 The calcium levels induced by TLCS were shown.

[0040] Figure 12 This shows the level of amylase release from mouse acinar cells. Detailed Implementation

[0041] The methods and compositions disclosed herein are used to regulate intracellular calcium to improve or prevent symptoms of pancreatitis. In some aspects, the pancreatitis is acute pancreatitis. In some aspects, the 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 aspects, the viral disease is hemorrhagic fever virus. In some aspects, the hemorrhagic fever virus is amphiboxvirus, fibrillin virus, Benyovirus, flavivirus, rhabdovirus, or combinations thereof. As non-limiting examples, hemorrhagic fever viruses include Ebola virus, Marburg virus, Lassa virus, Junin virus, rotavirus, West Nile virus, Zika virus, Coxsackie virus, hepatitis B virus, EB virus, etc. 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 aspects, the Th17-induced disease is an inflammatory disease. In further aspects, the Th17-induced disease is an autoimmune disease. In some aspects, the compounds provided herein regulate SOC channel activity. In some respects, the methods and compounds provided herein regulate CRAC channel activity. In other respects, the compounds provided herein regulate STIM protein activity. In other respects, the methods and compounds provided herein regulate Orai protein activity. In other respects, the methods and compounds provided herein regulate the functional interaction between STIM and Orai proteins. In other respects, the methods and compounds provided herein reduce the number of functional SOC channels. In other respects, the methods and compounds provided herein reduce the number of functional CRAC channels. In some respects, the methods and compounds described herein are SOC channel blockers. In some respects, the methods and compounds described herein are CRAC channel blockers or CRAC channel modulators.

[0042] Calcium plays a vital role in cell function and survival. For example, calcium is a key element in signal transduction into and within cells. Cellular responses to growth factors, neurotransmitters, hormones, and many other signaling molecules are initiated through calcium-dependent processes.

[0043] Almost all cell types depend on cytoplasmic calcium in some way. 2+ Signals are generated to regulate cellular function or trigger specific responses. Cytosol Ca2+ 2+ Signals control a range of cellular functions, encompassing everything from short-term responses such as contraction and secretion to long-term regulation of cell growth and proliferation. These signals are often involved in the release of calcium from intracellular calcium pools, such as the endoplasmic reticulum (ER). 2+ and Ca 2+Certain combinations of molecules flow across the plasma membrane. In one instance, cell activation begins with the binding of an agonist to a surface membrane receptor, which is coupled 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 the IP3 receptor, thereby causing Ca2+ uptake. 2+ Released from the ER. Ca in the ER 2+ The decrease then sends a signal to activate calcium pools in the plasma membrane that manipulate calcium (SOC) channels.

[0044] Calcium pool-manipulated calcium (SOC) influx is a cellular physiological process that controls a wide variety of functions, including, but not limited to, intracellular calcium. 2+ Cell refilling (Putney et al., Cell, 75, 199-201, 1993); activation of enzyme activity (Fagan et al., J. Biol. Chem. 275: 26530-26537, 2000); gene transcription (Lewis, Annu. Rev. Immunol. 19: 497-521, 2001); cell proliferation (Nunez et al., J. Physiol. 571.1, 57-73, 2006); and release of cytokines (Winslow et al., Curr. Opin. Immunol. 15: 299-307, 2003). In some non-excitable cells such as blood cells, immune cells, hematopoietic cells, T lymphocytes and mast cells, pancreatic acinar cells (PACs), epithelial and ductal cells of other glands (such as salivary glands), endothelial cells and endothelial progenitor cells, SOC influx occurs through calcium release-activated calcium (CRAC) channels (a type of SOC channel).

[0045] The calcium influx mechanism was once known as calcium pool-manipulated calcium influx (SOCE). Interstitial interaction molecule (STIM) proteins are essential components of SOC channel function, acting as sensors to detect the depletion of calcium from the intracellular calcium pool and to activate SOC channels.

[0046] Calcium homeostasis

[0047] Cellular calcium homeostasis is the result of a sum of regulatory systems involved in controlling intracellular calcium levels and movement. Cellular calcium homeostasis is achieved at least in part through calcium binding; through the movement of calcium across the plasma membrane into and out of the cell; and through 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.

[0048] Calcium movement across the cell membrane occurs through specialized proteins. For example, calcium from the extracellular space can enter the cell via various calcium channels and sodium / calcium exchangers, and can be actively expelled from the cell via calcium pumps and sodium / calcium exchangers. Calcium can also be released from the internal calcium pool via inositol triphosphate or ryanodine receptors and can be absorbed by these organelles using calcium pumps.

[0049] Calcium can enter cells through any of several common types of channels, including but not limited to voltage-operated calcium (VOC) channels, calcium pool-operated calcium (SOC) channels, and sodium / calcium exchangers operating in reverse mode. VOC channels are activated by membrane depolarization and are found in excitable cells such as nerve and muscle cells, but not in most inexcitable cells. Under certain conditions, Ca... 2+ It can be accessed via Na operating in reverse mode + -Ca 2+ Exchangers enter the cell.

[0050] Endocytosis provides another process through which cells can absorb calcium from the extracellular matrix via endosomes. Additionally, some cells, such as exocrine cells, can release calcium via exocytosis.

[0051] Cytosolic calcium concentration is tightly regulated to resting levels, typically estimated at approximately 0.1 μM in mammalian cells, while extracellular calcium concentration is usually around 2 mM. This tight regulation facilitates the transduction of signals into and within the cell via transient calcium flow across the plasma membrane and intracellular organelle membranes. Multiple intracellular calcium transport and buffering systems play a role in modulating intracellular calcium signaling and maintaining low resting cytosolic calcium concentrations. In resting cells, the key components involved in maintaining basal calcium levels are calcium pumps and leakage pathways in both the endoplasmic reticulum and plasma membrane. Perturbations in resting cytosolic calcium levels can affect calcium-dependent signaling and lead to defects in numerous cellular processes. For example, cell proliferation involves long-term calcium signaling sequences. Other cellular processes involving calcium signaling include, but are not limited to, secretion, transcription factor signaling, and fertilization.

[0052] Activation of phospholipase C (PLC) cell surface receptors produces cytosolic calcium from intracellular and extracellular sources. 2+ Signal. Due to the release of Ca from the endoplasmic reticulum (ER) 2+ And resulting in [Ca 2+ ] iThe initial transient increase in intracellular calcium concentration is initiated by the PLC product inositol-1,4,5-triphosphate (IP3), which opens the IP3 receptor in the ER (Streb et al., Nature, 306, 67-69, 1983). This is followed by a sustained increase in intracellular calcium concentration across the plasma membrane via specialized calcium pools in the plasma membrane (SOC channels; in the case of inexcitable cells such as immune PAC cells, these SOC channels are calcium release-activated calcium (CRAC) channels). 2+ The subsequent stages of inflow. Ca manipulated in the calcium pool. 2+ Internal flow (SOCE) is where Ca 2+ The emptying of the pool itself activates the Ca in the plasma membrane. 2+ Channels aid in the refilling of calcium pools (Putney, Cell Calcium, 7, 1-12, 1986; Parekh et al., Physiol. Rev. 757-810; 2005). SOCEs are not simply for providing calcium for refilling calcium pools. 2+ Rather, it is not that it can generate continuous Ca, but rather that it can generate Ca itself. 2+ Signals that control fundamental functions such as gene expression, cell metabolism, and exocytosis (Parekh and Putney, Physiol. Rev. 85, 757-810 (2005).

[0053] In lymphocytes and mast cells, activation of antigens or Fc receptors respectively induces Ca 2+ Release from intracellular calcium pools, leading to the release of calcium through CRAC channels in the plasma membrane. 2+ Inflow. Subsequently, intracellular Ca... 2+Elevated levels of NFAT activate calcineurin, a phosphatase that regulates the transcription factor NFAT. In resting cells, NFAT is phosphorylated and located in the cytoplasm, but when dephosphorylated by calcineurin, NFAT translocates to the nucleus and activates different genetic programs depending on the stimulus and cell type. In response to infection and during transplant rejection, NFAT works with the transcription factor AP-1 (Fos-Jun) in the nucleus of “effector” T cells, thereby transactivating cytokine genes, genes regulating T cell proliferation, and other genes that coordinate active immune responses (Rao et al., Annu Rev Immunol., 1997; 15:707-47). Conversely, in T cells that recognize self-antigens, NFAT is activated in the absence of AP-1 and activates a transcriptional program known as “anergy,” which suppresses the autoimmune response (Macian et al., Transcriptional mechanisms underlying lymphocyte tolerance. Cell. 2002, 14 June; 109(6):719-31). In a subset of T cells known as regulatory T cells (which suppress autoimmunity mediated by self-reactive effector T cells), NFAT collaborates with the transcription factor FOXP3 to activate genes responsible for repressive functions (Wu et al., Cell, July 28, 2006; 126(2):375-87; Rudensky AY, Gavin M, Zheng Y. Cell. July 28, 2006; 126(2):253-256).

[0054] The endoplasmic reticulum (ER) performs a variety of processes. The ER has the function of acting as a calcium... 2+ trough and agonist sensitivity Ca 2+ The function of the cavity, and protein folding / processing occurs within its lumen. In the latter case, numerous Ca... 2+ - Companion proteins ensure that newly synthesized proteins fold correctly and are transported to their appropriate destinations. ERs are also involved in vesicle transport, release of stress signals, regulation of cholesterol metabolism, and apoptosis. Many of these processes require intraluminal Ca2+. 2+ Furthermore, protein misfolding, ER stress response, and apoptosis can all be caused by prolonged depletion of Ca in the ER. 2+ And induction. Because it contains a limited amount of Ca. 2+ Clearly, Ca is released during the stimulation period. 2+ Afterwards, ER Ca 2+ The content should decrease. However, to maintain the functional integrity of the ER, Ca is crucial. 2+ The level should not be lowered too much, or at least should be maintained at a low level. Therefore, supplementing ER with Ca...2+ This is an important process for all eukaryotic cells. Because ER Ca 2+ The decrease in content activates the calcium pool in the plasma membrane to manipulate Ca. 2+ The channel, therefore, is considered to be Ca. 2+ The main function of the influx pathway is to maintain ER Ca2+, which is essential for proper protein synthesis and folding. 2+ Horizontal. However, the calcium pool manipulates the Ca... 2+ The channel has other important functions.

[0055] Electrophysiological studies have provided insights into calcium influx manipulated by calcium pools, identifying that the process of emptying calcium pools activates calcium in mast cells. 2+ Electric current, which is called Ca 2+ Release activated Ca 2+ Current or I CRAC I CRAC It is a non-voltage-activated, inwardly rectified current, and significantly more sensitive to Ca. 2+ It is selective. I has been found in several cell types that are primarily derived from hematopoiesis. CRAC I CRAC It is not the only current manipulated by calcium pools, and it is now clear that the inflow of calcium pools involves Ca with different properties in different cell types. 2+ - The permeability channel family. I CRAC This is the first type of calcium pool manipulation of Ca described. 2+ Current, and remains a popular model for studying the inflow of calcium pool manipulation.

[0056] It can be achieved by venting ER Ca 2+ Any procedure used to activate the calcium channels manipulated by the calcium pool is irrelevant; how the calcium pool is emptied seems to be irrelevant, the net effect is the calcium channel manipulated by the calcium pool. 2+ Activation of influx. Physiologically, this is caused by an increase in IP3 levels or other calcium... 2+ - The release signal induces the calcium pool to empty, followed by the release of Ca from the calcium pool. 2+ However, there are several other methods for emptying calcium pools. These methods include the following:

[0057] 1) Increase IP3 in cytosol (after receptor stimulation or by dialyzing cytosol with IP3 itself or related analogues such as the non-metabolizable analogue Ins(2,4,5)P3);

[0058] 2) Application of Ca 2+ Ion carriers (e.g., ionomycin) are used to permeate the ER membrane;

[0059] 3) Use high concentrations of Ca 2+A chelating agent (e.g., EGTA or BAPTA) is used to dialyze the cytoplasm, and the chelating agent chelates calcium that has leaked from the calcium pool. 2+ And thus prevent the calcium pool from being refilled;

[0060] 4) It interacts with sarcoplasmic reticulum / endoplasmic reticulum Ca2+, for example, thapsigargin, cyclopiazonic acid, and di-tert-butylhydroquinone. 2+ - ATPase (SERCA) inhibitor exposure;

[0061] 5) Sensitize IP3 receptors to resting levels of InsP3 using agents such as thimerosal; and

[0062] 6) The permeable metal Ca 2+ Chelating agents such as N,N,N',N'-tetra(2-pyridylmethyl)ethylenediamine (TPEN) are directly added to the calcium pool.

[0063] Through its mass effect, TPEN reduces free intracavitary Ca. 2+ Concentration without changing the total calcium pool Ca 2+ This generates a calcium pool depletion-dependent signal.

[0064] These methods of draining calcium pools have potential problems. 2+ The key characteristic of influx is that the channels are activated by Ca in the calcium pool. 2+ The decrease in content, rather than the subsequent decrease in cytoplasmic Ca 2+ Increased concentration. However, iodomycin and SERCA pump inhibitors typically cause cytoplasmic calcium depletion due to calcium pool exhaustion. 2+ As the concentration increases, this Ca... 2+ Elevation can open up the passage of Ca 2+ of, Ca 2+ Activated cation channels. One way to avoid this type of problem is to use high concentrations of Ca. 2+ Chelating agents such as EGTA or BAPTA strongly buffer cytoplasmic calcium. 2+ Use the drug under the specified conditions.

[0065] calcium influx manipulated by calcium pool

[0066] The decrease in calcium concentration caused by the release of calcium from intracellular calcium pools (such as the endoplasmic reticulum) provides the signal for calcium to flow into the cell from the extracellular matrix. This calcium influx (which produces a sustained “plateau” increase in cytosolic calcium concentration) typically does not rely on voltage-gated plasma membrane channels and does not involve calcium activation of these channels. This calcium influx mechanism is termed volumetric calcium influx (CCE), calcium release-activated, calcium pool-manipulated, or depletion-manipulated calcium influx. Calcium pool-manipulated calcium influx can be recorded as an ionic current with unique properties. This current is called Ic. SOC (Current manipulated by the calcium pool) or I CRAC (Calcium releases activated current).

[0067] Electrophysiological analysis of calcium pool-manipulated or calcium release-activated currents has revealed unique biophysical properties of these currents (see, for example, Parekh and Penner (1997) Physiol. Rev. 77:901-930). For instance, these currents can be activated by depletion of the intracellular calcium pool (e.g., by non-physiological activators such as carotenoids, CPA, iomycin, and BAPTA, and physiological activators such as IP3), and can be selective relative to monovalent ions to divalent cations such as calcium under physiological solutions or conditions, influenced by changes in cytosolic calcium levels, and exhibit altered selectivity and conductivity in the presence of low extracellular concentrations of divalent cations. These currents can also be blocked or enhanced by 2-APB (depending on concentration), and by SKF96365 and Gd. 3+ It is a blocking mechanism, and can generally be described as non-strictly voltage-gated.

[0068] Patch-clamp studies in mast cells and Jurkat leukemia T cells have identified the CRAC influx mechanism as an ion channel with unique biophysical properties, including pairing with Ca2+ cells with extremely low conductivity. 2+ High selectivity. Furthermore, it shows that the CRAC channel meets stringent criteria for calcium pool manipulation, being manipulated solely by Ca in the ER. 2+ The reduction in activation, without the influence of cytosol Ca2+, is due to the decrease in activation. 2+ Or other information generated by the PLC to activate (Prakriya et al., in Molecular and Cellular Insights into Ion Channel Biology (edited by Robert Maue) 121-140 (Elsevier Science, Amsterdam, 2004)).

[0069] Regulation of calcium influx by intracellular calcium pool

[0070] Calcium influx induced by the calcium pool is regulated by the calcium level within the intracellular calcium pool. The intracellular calcium pool can be characterized by sensitivity to agents, which can be physiological or pharmacological agents, that activate the release of calcium from the calcium pool or inhibit the uptake of calcium into the calcium pool. The characteristics of intracellular calcium pools in different cells have been studied, and these pools have been characterized as sensitive to a variety of agents, including but not limited to IP3 and compounds that affect the IP3 receptor, carotenoids, ionomycin, and / or cyclic ADP-ribose (cADPR) (see, for example, 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).

[0071] Calcium accumulation within the endoplasmic reticulum and sarcoplasmic reticulum (SR; a specialized form of the endoplasmic reticulum in skeletal muscle) is achieved through the sarcoplasmic reticulum-endoplasmic reticulum calcium ATPase (SERCA), commonly known as the calcium pump. During signal transduction (i.e., when endoplasmic reticulum channels are activated to provide calcium release from the endoplasmic reticulum into the cytoplasm), endoplasmic reticulum calcium is replenished by the SERCA pump with cytoplasmic calcium that has entered the cell from the extracellular matrix (Yu and Hinkle (2000) J. Biol. Chem. 275:23648-23653; Hofer et al. (1998) EMBO J. 17:1986-1995).

[0072] Calcium release channels associated with IP3 and rynocyanine receptors provide controlled release of calcium from the endoplasmic reticulum and sarcoplasmic reticulum into the cytoplasm, resulting in a transient increase in cytoplasmic calcium concentration. IP3 receptor-mediated calcium release is initiated by IP3, which is formed by the cleavage of plasma membrane phosphoinositol via the action of phospholipase C, which is activated by the binding of agonists to plasma membrane G protein-coupled receptors or tyrosine kinases. Ryanoid receptor-mediated calcium release, triggered by an increase in cytoplasmic calcium, is termed calcium-induced calcium release (CICR). The activity of rynocyanine receptors (which have an affinity for rynocyanines and caffeine) can also be regulated by cyclic ADP-ribose.

[0073] Therefore, calcium levels in the calcium pool and cytoplasm fluctuate. For example, when HeLa cells are treated with histamine (a PLC-linked histamine receptor agonist), the concentration of free calcium in the ER can decrease from approximately 60–400 μM to approximately 1–50 μM (Miyawaki et al. (1997) Nature 388:882–887). As the concentration of free calcium in the intracellular calcium pool decreases, calcium pool-manipulated calcium influx is activated. Therefore, calcium depletion from the calcium pool and the accompanying increase in cytosol calcium concentration can regulate calcium pool-manipulated calcium influx into the intracellular calcium pool.

[0074] Cytoplasmic calcium buffering

[0075] Agonist activation of cellular signaling processes can involve, for example, significantly increasing endoplasmic reticulum (ER) calcium permeability by opening IP3 receptor channels, and significantly increasing plasma membrane calcium permeability through calcium influx manipulated by calcium pools. These increases in calcium permeability are associated with increases in cytosolic calcium concentration, which can be divided into two components: a “spiking” phase of calcium release from the ER during IP3 receptor activation, and a plateau phase of sustained increases in calcium levels due to calcium influx from the extracellular matrix into the cytoplasm. Upon stimulation, the resting intracellular free calcium concentration of approximately 100 nM can rise to greater than 1 μM, and even higher within the cellular microdomain. Cells regulate these calcium signals using endogenous calcium buffers, including the physiological buffering of organelles such as mitochondria, the ER, and the Golgi apparatus. Mitochondrial calcium uptake via onewayports in the inner membrane is driven by a large, negative mitochondrial membrane potential, and accumulated calcium is slowly released through sodium-dependent and non-sodium-dependent exchangers, and in some cases, through the permeability transition pore (PTP). Therefore, mitochondria act as calcium buffers by absorbing calcium during cell activation and then slowly releasing it later. Calcium uptake into the endoplasmic reticulum is regulated by sarcoplasmic reticulum and endoplasmic reticulum calcium ATPase (SERCA). Calcium uptake into the Golgi apparatus is mediated by P-type calcium transport ATPase (PMR1 / ATP2C1). Additionally, there is evidence that a significant amount of calcium released upon IP3 receptor activation is expelled from the cell via plasma membrane calcium ATPases. For example, plasma membrane calcium ATPases provide the dominant calcium clearance mechanism in human T cells and Jurkat cells, although sodium / calcium exchange also contributes to calcium clearance in human T cells. Within calcium-storing organelles, calcium ions can bind to specialized calcium-buffering proteins such as calcitonin, calreticulin, and calconin. Furthermore, calcium-buffering proteins exist in the cytosol that regulate calcium spikes and facilitate calcium ion redistribution. Therefore, proteins and other molecules involved in any of these and other mechanisms (through which they can reduce cytosol calcium levels) are proteins involved in, participate in, and / or provide cytosol calcium buffering. Therefore, the cytoplasmic calcium buffering function plays a crucial role in the continuous calcium inflow through SOC channels or Ca 2+Release burst helps regulate cytoplasmic Ca 2+ Level. Cytoplasmic Ca 2+ A significant increase in levels or refilling of the calcium pool can deactivate SOCE.

[0076] Downstream calcium influx-mediated events

[0077] Besides changes in the intracellular calcium pool, calcium pool-manipulated calcium influx also affects many events that are either a result of changes in calcium pool manipulation or events that occur independently of changes in calcium pool manipulation. For example, Ca... 2+ The influx of calcium leads to the activation of numerous calmodulin-dependent enzymes, including serine phosphatase and calmodulin. Increased intracellular calcium activation of calmodulin triggers acute secretory processes such as mast cell degranulation. Activated mast cells release pre-formed granules containing histamine, heparin, TNFα, and enzymes such as β-aminohexosidase. Certain cellular events, such as B and T cell proliferation, require sustained calmodulin signaling, which necessitates a sustained increase in intracellular calcium. Several transcription factors are regulated by calmodulin, including NFAT (activating T cell nuclear factor), MEF2, and NFκB. NFAT transcription factors play important roles in many cell types, including immune cells. In immune cells, NFAT mediates the transcription of a large number of molecules, including cytokines, chemokines, and cell surface receptors. Transcriptional elements targeting NFAT have been found in the promoters of cytokines such as IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, as well as tumor necrosis factor α (TNFα), granulocyte colony-stimulating factor (G-CSF), and gamma-interferon (γ-IFN).

[0078] The activity of NFAT protein is regulated by its phosphorylation level, which in turn is regulated by both calmophosphatase and NFAT kinase. Increased intracellular calcium levels activate calmophosphatase, leading to NFAT dephosphorylation and its entry into the nucleus. Rephosphorylation of NFAT masks its nuclear localization sequence and prevents its entry into the nucleus. Because its localization and activity are strongly dependent on calmophosphatase-mediated dephosphorylation, NFAT is a sensitive indicator of intracellular free calcium levels.

[0079] Calcium channel inhibitors

[0080] This document discloses a variety of calcium channel inhibitors consistent with the methods, compositions, administration regimens, and compositions used for the purposes 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.

[0081] In some embodiments, the compound is a compound having the following structure:

[0082] Or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the compound is selected from N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects, the intracellular calcium signaling inhibitor is the compound N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide thereof, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some respects, this intracellular calcium signaling inhibitor is selected from the following compounds: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(4-(1-ethyl-3-(thiazolyl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl) -2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazol-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5 ... 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1-methyl-1H-pyrazol-5-carboxamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl))methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxane-[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluoro Benzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-Trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazolin-2-yl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro) 4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0083] Calcium signaling and pancreatic health

[0084] Calcium signaling is central to healthy pancreatic activity. Food stimulates the release of acetylcholine (ACh) and cholecystokinin (CCK), which interact with receptors linked to phospholipase C (PLC) on pancreatic acinar cells (PACs). In healthy PACs, ACh or CCK receptors trigger the formation of IP3 (1,4,5-inositol triphosphate), which diffuses to the apical region and stimulates IP3 receptors on the endoplasmic reticulum (ER) to release calcium in a controlled pulsatile manner. 2+ Ca 2+ Fluctuations stimulate the release of pro-enzymes into the pancreatic duct. Over time, ER Ca 2+ This needs to be replenished, which is achieved through the gentile activation of CRAC channels in the basal outer region of the cell.

[0085] In certain situations (e.g., alcohol poisoning or alcoholism, gallstones, etc.), fatty acid ethyl esters (FAEEs) formed from alcohol or bile acids accumulated due to gallstones diffuse into the PAC. Within the PAC, FAEEs and bile acids cause ER Ca2+ by activating IP3 receptors. 2+ The large-scale release of calcium. Overstimulation of CCK receptors can also cause the release of stable calcium from the ER calcium pool. 2+ Release. Ca 2+ Pool emptying leads to overactivation of CRAC channels, thereby causing Ca 2+ Excessive inflow. Large amounts of Ca. 2+The influx leads to the release of enzymes from zymogen granules and inappropriate activation of intracellular trypsin, which in turn activates other pancreatic digestive enzymes and triggers autodigestion and necrosis of the pancreas. This autodigestion and necrosis can be blocked by CRAC channel inhibitors such as Compound I, GSK-7975A, N-(5-(2,5-dimethylbenzo[d]oxazol-6-yl)thiazo-2-yl)-2,3,6-trifluorobenzamide (“Compound II”) or 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide (“Compound III”).

[0086] Inappropriate release and activation of digestive enzymes such as trypsin from zymogen granules, if left unresolved, can lead to autodigestion of pancreatic cells, resulting in pancreatitis. As mentioned above, acute or chronic pancreatitis can have significant negative impacts on an individual's health.

[0087] Symptoms and causes of pancreatitis

[0088] Acute or chronic pancreatitis is associated with severe upper abdominal or left upper quadrant burning pain radiating to the back, nausea, and vomiting that worsens with eating. Internal bleeding may also occur, depending on the severity of the condition. Blood pressure, heart rate, and respiratory rate are usually elevated, although dehydration can cause a decrease in blood pressure rather than an increase. The abdomen is usually tender, less so than the pancreas itself. Reflex paralytic ileus is commonly observed in pancreatitis, and fever or jaundice is not uncommon. Common symptoms and signs of pancreatitis include: severe upper abdominal pain radiating to the back (upper abdominal pain), nausea, vomiting, loss of appetite, fever, chills (shivering), hemodynamic instability (including shock), tachycardia (rapid heartbeat), respiratory distress, and peritonitis.

[0089] Less commonly observed symptoms indicating serious illness include several medical “signs” indicating severe abdominal pain: Grey-Turner’s sign (hemorrhagic discoloration of the flank), Cullen’s sign (hemorrhagic discoloration of the umbilicus), pleural effusion (fluid in the base of the pleural cavity), Grünwald’s sign (ecchymosis near the umbilicus due to local toxic damage to blood vessels, large contusion), and Kotter’s sign (…). The signs include: pain or tenderness in the upper part of the pancreas (upper abdomen, 6-7 cm above the umbilicus), Kamenchik's sign (pressure pain below the xiphoid process), and Mayo-Robson's sign (pain upon pressure at the top of the angle with the erector spinae muscle and below the left twelfth rib (left costovertebral angle (CVA)). Mayo-Robson's point (the point where the inner 2 / 3 and outer 1 / 3 of the bisector of the left upper quadrant meet, where tenderness upon pressure is present in pancreatic disorders. At this point, the tail of the pancreas projects onto the abdominal wall).

[0090] People with pancreatitis may experience some or all of the above symptoms, or none at all. In some cases, abdominal pain may be the only symptom of the disease.

[0091] Chronic pancreatitis can lead to diabetes or pancreatic cancer. Defects in the delivery of digestive enzymes such as trypsin can cause indigestion, which in turn can lead to weight loss.

[0092] Up to 80 percent of pancreatitis cases are caused by alcohol and gallstones. Gallstones are the single most common cause of acute pancreatitis. Alcohol is the single most common cause of chronic pancreatitis.

[0093] However, besides alcohol and gallstones, there are several other causes of pancreatitis. Some medications may be associated with pancreatitis. Examples of medications associated with pancreatitis include corticosteroids such as prednisolone, HIV medications such as norinosine and pentazocine, diuretics, anticonvulsants such as valproic acid, chemotherapy agents such as L-asparaginase and azathioprine, estrogens, medications that increase blood triglycerides, statins such as cholesterol-lowering statins, antiglycemic agents such as metformin and gliptins such as vildagliptin, sitagliptin, saxagliptin, and linagliptin, tetracyclines, sulfonamides, azathioprine, mercaptopurine, pentazocine, trimethoprim-sulfamethoxazole, and salicylates. In some cases, medications used to treat symptoms associated with an increased risk of pancreatitis events may also incidentally be associated with pancreatitis. Examples include statins for dyslipidemia and gliptins for diabetes. In addition, some atypical antipsychotics such as clozapine, risperidone, and olanzapine can also cause pancreatitis. This list is not exhaustive.

[0094] Non-pharmacological causes of pancreatitis are also known. For example, hereditary forms of pancreatitis are known to lead to the activation of trypsinogen within the pancreas, resulting in autodigestion. Genes associated with heritable pancreatitis include trypsin1, which encodes trypsinogen; SPINK1, which encodes a trypsin inhibitor; and transmembrane conduction regulators of cystic fibrosis.

[0095] Other common non-pharmacological causes of pancreatitis include trauma, mumps, autoimmune diseases, hypercalcemia, hypothermia, and endoscopic retrograde cholangiopancreatography (ERCP). Pancreatic mitosis is a common congenital pancreatic malformation and can be the basis for some recurrent cases. Penetrating ulcers are also associated with pancreatitis. Type 2 diabetes is associated with a 2.8-fold higher risk of developing pancreatitis symptoms. Other conditions associated with pancreatitis include pancreatic cancer, pancreatic duct stones, vasculitis (inflammation of small blood vessels in the pancreas), Coxsackie virus infection, and porphyria, particularly acute intermittent porphyria and erythropoietic protoporphyria. In some cases, pregnancy is associated with pancreatitis. Repetitive marathon exercise, anorexia and bulimia, as well as fat necrosis, cystic fibrosis, and scorpion venom are also associated with some cases of pancreatitis.

[0096] Many infectious agents are associated with pancreatitis. Examples include viral infections such as cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps virus, and varicella-zoster virus; bacterial infections such as Legionella, Leptospira, Mycoplasma, or Salmonella; fungal infections such as Aspergillus; or parasitic infections such as Ascaris lumbricoides (nematodes) or Cryptosporidium (astrosolates) and Toxoplasma gondii; and so on.

[0097] Medical students often use the mnemonic "GETSMASHED" to remember some 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 - medications, usually azathioprine or valproic acid.

[0098] Pancreatitis can also be idiopathic, in which case the cause cannot be identified.

[0099] Classification of pancreatitis

[0100] Based on the primary response to cellular damage, pancreatitis, especially acute pancreatitis, is often classified as "mild," "moderate," or "severe." All these categories are characterized by the misactivation of pancreatic zymogens, such as trypsinogen, within the pancreas. This misactivation is usually due to co-localization with the trypsinogen maturation enzyme cathepsin, which activates trypsinogen into trypsin. All three categories are characterized by inflammation and edema of the pancreas. Moderate and severe pancreatitis are further characterized by pancreatic necrosis and secondary damage to extrapancreatic organs. Patients with moderate acute pancreatitis experience transient (<48 hours) organ failure, while those with severe acute pancreatitis experience persistent (>48 hours) organ failure.

[0101] To address the aforementioned issues, the pancreas can directly synthesize inflammatory mediators such as TNF-α and IL-1, which is associated with the inflammatory response and the recruitment of neutrophils to the pancreas, or due to the necrosis and leakage of cellular components that otherwise activate the immune system. The inflammatory response may lead to secondary manifestations of pancreatitis, such as hypovolemia due to capillary permeability, acute respiratory distress syndrome, disseminated intravascular coagulation, renal failure, cardiovascular failure, and gastrointestinal bleeding.

[0102] Acute pancreatitis (acute hemorrhagic pancreatic necrosis) is further characterized by acute inflammation and necrosis of the pancreatic parenchyma, focal enzymatic necrosis of pancreatic fat, and vascular necrosis (hemorrhagic necrosis) resulting from intrapancreatic activation of pancreatic enzymes. Lipase activation can lead to necrosis of adipose tissue in the pancreatic interstitium and peripancreatic spaces, as well as vascular damage. Digestion of the vascular walls leads to thrombosis and hemorrhage. Inflammatory infiltrates are rich in neutrophils. Because the pancreas lacks a sac, inflammation and necrosis can extend to the fascia layer immediately adjacent to the pancreas.

[0103] Chronic pancreatitis is a long-term inflammation of the pancreas that alters the normal structure and function of the organ. It may be associated with an acute pancreatitis attack or persistent abdominal pain or digestive problems. Patients with chronic pancreatitis often present with persistent abdominal pain or malabsorption of fats from food. Pain is also common during food intake, especially during the consumption of fatty or high-protein foods. Weight loss is also common due to malabsorption of food or reduced food intake caused by discomfort.

[0104] A common complication of chronic pancreatitis is diabetes.

[0105] Alcohol poisoning, smoking, malnutrition, trauma, hypercalcemia, calcified stones, cystic fibrosis, and genetic defects in trypsinogen processing and stability are often associated with chronic pancreatitis.

[0106] Chronic pancreatitis is usually diagnosed based on tests of pancreatic structure and function. Because the extent of damage to productive cells is uncertain, serum amylase and lipase may or may not be moderately elevated in cases of chronic pancreatitis. Elevated lipase is the more likely finding of the two. Elevated amylase and lipase, along with elevated CRP inflammatory markers generally consistent with the severity of the condition, are almost always found in acute cases.

[0107] The secretin stimulation test is perhaps the most accurate functional test for diagnosing chronic pancreatitis. Impaired bicarbonate production in the early stages of chronic pancreatitis is used to identify individuals in the early stages of the disease (sensitivity 95%). Other tests used to determine chronic pancreatitis include fecal elastase measurement, serum trypsinogen, computed tomography (CT), ultrasound, EUS, MRI, ERCP, and MRCP. Abdominal X-rays and CT scans may reveal pancreatic calcifications. However, it is important to note that ERCP and X-rays may trigger acute pancreatitis.

[0108] Many other tests can be used to diagnose chronic pancreatitis. Elevated serum bilirubin and alkaline phosphatase levels can indicate chronic pancreatitis, and in some cases, common bile duct stenosis due to edema, fibrosis, or cancer. Chronic pancreatitis associated with an autoimmune response may be accompanied by elevated ESR, IgG4, rheumatoid factor, ANA, and anti-smooth muscle antibodies; any one of these measurements can indicate chronic pancreatitis in a person. Typical symptoms of chronic pancreatitis, steatorrhea, or malabsorption can be diagnosed by two different studies: Sudan chemical staining of stool or the excretion of 7 grams or more of fecal fat within 24 hours after a 100g fat diet. To examine pancreatic exocrine dysfunction, an exemplary test of sensitivity and specificity is the measurement of fecal elastase, which can be performed with a single stool sample, and a value less than 200 μg / g indicates pancreatic insufficiency.

[0109] Several methods are known for assessing the severity of pancreatitis in individuals. Common tests include BISAP, Ranson's test, APACHE-II, and CTSI. For example, the BISAP test is based on the following criteria assessed within the first 24 hours after admission: blood urea nitrogen >25 mg / dL (8.92 mmol / L); impaired mental status, defined as disorientation, stupor, lethargy, coma, or stupor; ≥2 criteria for systemic inflammatory response syndrome; age >60 years; and presence of pleural effusion. A positive assessment of any of these criteria produces a "score" on a total scale ranging from 0 to 5. In some implementations of the test, mortality rates range from less than 1% in the lowest risk group to more than 20% in the highest risk group.

[0110] Many references discuss tests for pancreatitis severity, each of which is incorporated into this paper 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.Published online June 2, 2008. 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.Published online on 27 October 2009. PubMed PMID:19861954; and

[0111] Gompertz M, Fernández L, Lara I, Miranda JP, Mancilla C, Berger Z. [Bedsideindex for severity in acute pancreatitis (BISAP) score as predictor of clinical outcome in acute pancreatitis: retrospective review of 128patients].Rev MedChil. 2012 Aug;140(8):977-83.doi:10.1590 / S0034-98872012000800002.Spanish.PubMed PMID:23282769.

[0112] Improvement in the treatment of pancreatitis

[0113] This document discloses compositions and methods for therapeutically improving pancreatitis and its symptoms, such as by administering calcium channel inhibitors like CRAC inhibitors. In some embodiments, the pancreatitis is acute pancreatitis. In some embodiments, the pancreatitis is chronic pancreatitis. In some embodiments, a method for improving pancreatitis symptoms in a person is disclosed. In some embodiments, a method for improving pancreatitis symptoms in a person is disclosed, comprising the steps of: identifying a person who needs improvement of pancreatitis symptoms; and administering an intracellular calcium signaling inhibitor to the person at a dose sufficient to improve the symptoms.

[0114] For example, individuals can be identified using common tests for pancreatitis symptoms such as BISAP, Lanssen's test, APACHE-II, and CTSI. The test may be BISAP. The test may be Lanssen's test. The test may be APACHE II. The test may be CTSI. In some embodiments, individuals with a BISAP score of 5, 4, 3, 2, or 1 are identified as individuals requiring improvement of pancreatitis symptoms. In some embodiments, individuals with a BISAP score of 2 are identified. In some embodiments, individuals with a BISAP score of 3 are identified. In some embodiments, individuals with a BISAP score of 4 are identified. In some embodiments, individuals with a BISAP score of 5 are identified. In some embodiments, individuals with at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 pancreatitis symptoms (as disclosed herein) are identified. In some embodiments, the subject is a non-human mammal instead of a human.

[0115] In some embodiments, the symptoms are those of acute pancreatitis. In some embodiments, the symptoms are those of chronic pancreatitis.

[0116] The symptoms may include at least one of the following: abdominal pain, elevated blood amylase levels, elevated blood lipase levels, enlarged pancreas, nausea, vomiting, internal bleeding, paralytic ileus, fever, jaundice, weight loss, and elevated heart rate. The symptoms may also include premature activation of digestive enzymes. For example, premature activation of a digestive enzyme may occur in the pancreas of the person. In some embodiments, the enzyme includes trypsin.

[0117] 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, improving the symptoms of pancreatitis further comprises administering an analgesic. In some embodiments, improving the symptoms of pancreatitis further comprises administering an analgesic, wherein the analgesic comprises opium. In some embodiments, improving the symptoms of pancreatitis further comprises administering an analgesic, wherein the analgesic comprises morphine. In some embodiments, improving the symptoms of pancreatitis further comprises administering an analgesic, wherein the analgesic comprises fentanyl. In some embodiments, improving the symptoms of pancreatitis further comprises administering an analgesic, wherein the analgesic comprises tramadol. In some implementations, improving the symptoms of pancreatitis further includes administering analgesics, including meperidine.

[0118] In some embodiments, an intracellular calcium signaling inhibitor is delivered to achieve an in vitro IC50 value equal to, approximately equal to, or greater than that measured against the compound. 50 The tissue level concentration is a value. In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which is a value determined in vitro for the compound at an IC50 concentration. 50Values ​​of 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 40 times, 41 times, 42 times, 43 times, 44 times, 45 times, 46 times, 47 times, 48 ​​times, 49 times, 50 times, 51 times, 52 times, 53 times. 54 times, 55 times, 56 times, 57 times, 58 times, 59 times, 60 times, 61 times, 62 times, 63 times, 64 times, 65 times, 66 times, 67 times, 68 times, 69 times, 70 times, 71 times, 72 times, 73 times, 74 times, 75 times, 76 times, 77 times, 78 times, 79 times, 80 times, 81 times, 82 times, 83 times, 84 times, 85 times, 86 times, 87 times, 88 times, 89 times, 90 times, 91 times, 92 times, 93 times, 94 times, 95 times, 96 times, 97 times, 98 times, 99 times, 100 times, or any non-integer multiple within the range of 1 to 100 times.

[0119] In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which ranges from the in vitro IC50 concentration measured against the compound. 50 The value is 1 to 100 times, 2 to 80 times, 3 to 60 times, 4 to 50 times, 5 to 45 times, 6 to 44 times, 7 to 43 times, 8 to 43 times, 9 to 41 times, or 10 to 40 times, or any non-integer within the range.

[0120] In some embodiments, calcium signaling inhibitors are delivered to achieve specific tissue 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, and 22 μM. μM, 23μM, 24μM, 25μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 3 6μM, 37μM, 38μM, 39μM, 40μM, 41μM, 42μM, 43μM, 44μM, 45μM, 46μM, 47μM, 48μM, 49μM, 5 0μM, 51μM, 52μM, 53μM, 54μM, 55μM, 56μM, 57μM, 58μM, 59μM, 60μM, 61μM, 62μM, 63μM, 64μM, 65μM, 66μM, 67μM, 68μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, 82μM, 83μM, 84μM, 85μM, 86μM, 87μM, 88μM, 89μM, 90μM, 91μM, 92μM, 93μM, 94μM, 95μM, 96μM, 97μM, 98μM, 99μM, 100μM, or any non-integer in the range of about 1μM to about 100μM.

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

[0122] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue level concentrations of 9.5 μM to 10.5 μM, 9 μM to 11 μM, 8 μM to 12 μM, 7 μM to 13 μM, 5 μM to 15 μM, 2 μM to 20 μM, or 1 μM to 50 μM, or any integer or non-integer concentration within the range.

[0123] In some embodiments, improvement in pancreatitis includes reducing the severity of at least one pancreatitis symptom. In some embodiments, improvement in pancreatitis includes reducing the severity of at least one pancreatitis symptom such that the symptom no longer affects the previously ill person. In some embodiments, improvement includes alleviating at least one symptom so that it has no effect on the person. In some embodiments, improvement includes a reduction of the symptoms by 10%, 20%, 30%, 40%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some embodiments, improvement includes reducing the severity of many symptoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 symptoms, up to and including all symptoms), said reduction including a reduction of the symptoms by 10%, 20%, 30%, 40%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%.

[0124] In some implementations, the improvement includes preventing the progression of pancreatitis, such as acute or chronic pancreatitis, so that more serious symptoms, such as organ failure, pancreatic necrosis, or death, do not occur.

[0125] Preventive improvement of acute and chronic pancreatitis

[0126] This document discloses compositions and methods for prophylactically improving acute pancreatitis and its symptoms, such as by administering calcium channel inhibitors like CRAC inhibitors. In some embodiments, a method for improving pancreatitis symptoms in a person is disclosed. In some embodiments, a method for improving pancreatitis symptoms in a person is disclosed, comprising the steps of: identifying a person who needs prophylactic improvement of pancreatitis symptoms; and administering an intracellular calcium signaling inhibitor to the person at a dose sufficient to prophylactically improve the symptoms.

[0127] 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, improving the symptoms of pancreatitis further comprises administering an analgesic such as opium. In some embodiments, morphine is an exemplary analgesic.

[0128] In some embodiments, an intracellular calcium signaling inhibitor is delivered to achieve an in vitro IC50 value equal to, approximately equal to, or greater than that measured against the compound. 50The tissue level concentration is a value. In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which is a value determined in vitro for the compound at an IC50 concentration. 50 Values ​​of 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 40 times, 41 times, 42 times, 43 times, 44 times, 45 times, 46 times, 47 times, 48 ​​times, 49 times, 50 times, 51 times, 52 times, 53 times, 5 4 times, 55 times, 56 times, 57 times, 58 times, 59 times, 60 times, 61 times, 62 times, 63 times, 64 times, 65 times, 66 times, 67 times, 68 times, 69 times, 70 times, 71 times, 72 times, 73 times, 74 times, 75 times, 76 times, 77 times, 78 times, 79 times, 80 times, 81 times, 82 times, 83 times, 84 times, 85 times, 86 times, 87 times, 88 times, 89 times, 90 times, 91 times, 92 times, 93 times, 94 times, 95 times, 96 times, 97 times, 98 times, 99 times, 100 times, or any non-integer multiple in the range of 1 to 100 times.

[0129] In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which is measured in vitro at an IC50 concentration against the compound. 50 The value is within the range of 1 to 100 times, 2 to 80 times, 3 to 60 times, 4 to 50 times, 5 to 45 times, 6 to 44 times, 7 to 43 times, 8 to 43 times, 9 to 41 times, or 10 to 40 times, or any non-integer within the range.

[0130] In some embodiments, calcium signaling inhibitors are delivered to achieve specific tissue 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, and 22 μM. μM, 23μM, 24μM, 25μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 3 6μM, 37μM, 38μM, 39μM, 40μM, 41μM, 42μM, 43μM, 44μM, 45μM, 46μM, 47μM, 48μM, 49μM, 5 0μM, 51μM, 52μM, 53μM, 54μM, 55μM, 56μM, 57μM, 58μM, 59μM, 60μM, 61μM, 62μM, 63μM, 64μM, 65μM, 66μM, 67μM, 68μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, 82μM, 83μM, 84μM, 85μM, 86μM, 87μM, 88μM, 89μM, 90μM, 91μM, 92μM, 93μM, 94μM, 95μM, 96μM, 97μM, 98μM, 99μM, 100μM, or any non-integer in the range of about 1μM to about 100μM.

[0131] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue level concentrations of 1 μM to 100 μM, 2 μM to 90 μM, 3 μM to 80 μM, 4 μM to 70 μM, 5 μM to 60 μM, 6 μM to 50 μM, 7 μM to 40 μM, 8 μM to 30 μM, 9 μM to 20 μM, or 10 μM to 40 μM, or any integer or non-integer concentration within the range.

[0132] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue level concentrations of 9.5 μM to 10.5 μM, 9 μM to 11 μM, 8 μM to 12 μM, 7 μM to 13 μM, 5 μM to 15 μM, 2 μM to 20 μM, or 1 μM to 50 μM, or any integer or non-integer concentration within the range.

[0133] In some embodiments, the method includes preventively improving symptoms of acute pancreatitis. In some embodiments, the method includes preventively improving symptoms of chronic pancreatitis.

[0134] Preventively improving pancreatitis symptoms may include reducing the severity, likelihood, or duration of at least one pancreatitis symptom. This may be done until the at least one symptom is no longer present in the person. In some embodiments, preventively improving pancreatitis symptoms may include reducing the severity, likelihood, or duration of two, three, four, five, six, seven, eight, nine, or more than nine pancreatitis symptoms, up to and including reducing the severity, likelihood, or duration of all pancreatitis symptoms (such as those disclosed herein) in a person. In some embodiments, the subject is a non-human mammal instead of a human.

[0135] In some embodiments, the person is diagnosed with gallstones. In some embodiments, the person exhibits symptoms of gallstones, such as pain in the upper right abdomen, for example, severe pain, and / or nausea and vomiting, which can steadily increase from about 30 minutes to several hours. The patient may also experience pain between the shoulder blades or below the right shoulder.

[0136] In some implementations, the person suffers from alcohol poisoning. In some implementations, the person suffers from chronic alcoholism. In some implementations, the person has suffered from at least one case of acute alcohol poisoning.

[0137] In some implementations, subjecting the person to a medication regimen includes administration of at least one of the following: steroids, such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone, and olanzapine.

[0138] In some embodiments, the person is identified as carrying a genetic form of pancreatitis. In some embodiments, the person carries a mutant allele of trypsin 1 associated with hereditary pancreatitis. In some embodiments, the person carries a trypsinogen variant associated with pancreatitis. In some embodiments, the person carries a mutant allele of SPINK1 associated with hereditary pancreatitis. In some embodiments, the person carries a mutant allele of a transmembrane conduction regulator of cystic fibrosis associated with hereditary pancreatitis.

[0139] In some implementations, the person has at least one of the following conditions: hypercalcemia, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic dysplasia, congenital pancreatic malformation, type 2 diabetes, pancreatic cancer, pancreatic duct stones, vasculitis, pancreatic small vessel inflammation, Coxsackie virus infection, and porphyria, such as acute intermittent porphyria and erythropoietic protoporphyria.

[0140] In some implementations, the person's physical health has been affected by at least one of the following: gallstones, alcohol poisoning, alcohol poisoning, trauma, mumps, autoimmune disease, scorpion sting, hyperlipidemia, hypothermia, hyperparathyroidism, endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid.

[0141] In some embodiments, the person's health condition has been affected by at least one of the following: Coxsackievirus, cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella bacteria, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungi, Ascaris parasites, Cryptosporidium cells, and Toxoplasma cells.

[0142] Combined use with drugs associated with pancreatitis

[0143] This document 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 administering to an individual a drug associated with negative effects on pancreatic activity, as well as administering an intracellular calcium signaling inhibitor.

[0144] In some implementations, the drugs associated with negative effects on pancreatic activity are selected from the following list: steroids such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone and olanzapine, azathioprine and valproic acid.

[0145] In some embodiments, the intracellular calcium signaling inhibitor is a SOC inhibitor. In some embodiments, the intracellular calcium signaling inhibitor is a CRAC inhibitor. An exemplary CRAC inhibitor includes compound I. An exemplary CRAC inhibitor includes GSK-7975A. An exemplary CRAC inhibitor includes compound II. An exemplary CRAC inhibitor includes compound III.

[0146] In some embodiments, the administration regimen includes administering a calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III, in combination with a drug associated with negative effects on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III, is administered on the same day as a drug associated with negative effects on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III, is administered in the same week as a drug associated with negative effects on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III, is administered concurrently with a drug associated with negative effects on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III, is administered in an administration regimen independent of the administration regimen of the drug associated with negative effects on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III, is administered via the same route of delivery as the drug associated with negative effects on pancreatic activity, such as oral or intravenous administration. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III, is administered via a different route of delivery than the drug associated with negative effects on pancreatic activity. In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III, is administered to the person receiving the drug associated with negative effects on pancreatic activity only after the person exhibits at least one indication of the drug's effect on pancreatic activity (e.g., by an increase in blood amylase activity or blood lipase activity, or by the presentation of at least one form of pancreatitis symptom as disclosed herein). In some embodiments, in the absence of any evidence relating to the effect of the drug on pancreatic activity in a person receiving the drug that is associated with a negative effect on pancreatic activity (e.g., by an increase in blood amylase activity or blood lipase activity or by the manifestation of at least one pancreatitis symptom as disclosed herein), the person is given a calcium channel inhibitor such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III.

[0147] In some embodiments, the calcium channel inhibitor, such as a CRAC inhibitor, such as at least one of compound I, GSK7975A, compound II, and compound III, is administered in a single composition along with a drug associated with negative effects on pancreatic activity. Therefore, some embodiments disclosed herein relate to a composition comprising an intracellular calcium signaling inhibitor and at least one drug associated with negative effects on pancreatic activity. In some embodiments, the at least one drug is selected from the following list: steroids such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone and olanzapine, azathioprine and valproic acid.

[0148] 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.

[0149] In some embodiments, an intracellular calcium signaling inhibitor is delivered to achieve an in vitro IC50 value equal to, approximately equal to, or greater than that measured against the compound. 50 The tissue level concentration is a value. In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which is a value determined in vitro for the compound at an IC50 concentration. 50Values ​​of 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 40 times, 41 times, 42 times, 43 times, 44 times, 45 times, 46 times, 47 times, 48 ​​times, 49 times, 50 times, 51 times, 52 times, 53 times, 5 4 times, 55 times, 56 times, 57 times, 58 times, 59 times, 60 times, 61 times, 62 times, 63 times, 64 times, 65 times, 66 times, 67 times, 68 times, 69 times, 70 times, 71 times, 72 times, 73 times, 74 times, 75 times, 76 times, 77 times, 78 times, 79 times, 80 times, 81 times, 82 times, 83 times, 84 times, 85 times, 86 times, 87 times, 88 times, 89 times, 90 times, 91 times, 92 times, 93 times, 94 times, 95 times, 96 times, 97 times, 98 times, 99 times, 100 times, or any non-integer multiple in the range of 1 to 100 times.

[0150] In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which is measured in vitro at an IC50 concentration against the compound. 50 The value is within the range of 1 to 100 times, 2 to 80 times, 3 to 60 times, 4 to 50 times, 5 to 45 times, 6 to 44 times, 7 to 43 times, 8 to 43 times, 9 to 41 times, or 10 to 40 times, or any non-integer within the range.

[0151] In some embodiments, calcium signaling inhibitors are delivered to achieve specific tissue 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, and 22 μM. μM, 23μM, 24μM, 25μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 3 6μM, 37μM, 38μM, 39μM, 40μM, 41μM, 42μM, 43μM, 44μM, 45μM, 46μM, 47μM, 48μM, 49μM, 5 0μM, 51μM, 52μM, 53μM, 54μM, 55μM, 56μM, 57μM, 58μM, 59μM, 60μM, 61μM, 62μM, 63μM, 64μM, 65μM, 66μM, 67μM, 68μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, 82μM, 83μM, 84μM, 85μM, 86μM, 87μM, 88μM, 89μM, 90μM, 91μM, 92μM, 93μM, 94μM, 95μM, 96μM, 97μM, 98μM, 99μM, 100μM, or any non-integer in the range of about 1μM to about 100μM.

[0152] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue level concentrations of 1 μM to 100 μM, 2 μM to 90 μM, 3 μM to 80 μM, 4 μM to 70 μM, 5 μM to 60 μM, 6 μM to 50 μM, 7 μM to 40 μM, 8 μM to 30 μM, 9 μM to 20 μM, or 10 μM to 40 μM, or any integer or non-integer concentration within the range.

[0153] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue level concentrations of 9.5 μM to 10.5 μM, 9 μM to 11 μM, 8 μM to 12 μM, 7 μM to 13 μM, 5 μM to 15 μM, 2 μM to 20 μM, or 1 μM to 50 μM, or any integer or non-integer concentration within the range.

[0154] In some embodiments, the composition further comprises at least one of an excipient, a solubilizer, a surfactant, a disintegrant, and a buffer solution. 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.

[0155] Calcium signaling and viral diseases

[0156] Viral diseases occur when an organism's body (the host) is invaded by a pathogenic virus. Infectious viral particles, called virions, attach to and enter susceptible cells in the host. Calcium signaling regulates viral entry, production, and spread within host cells, thereby disseminating viral diseases. For example, host cell calcium signaling is triggered by viral diseases through the activation of STIM1 and Orai-mediated calcium influx, which further allows the virus to bud and replicate within the host cell.

[0157] Viral diseases are diverse and can be classified according to structural characteristics such as genome type, virion shape, and replication site. As specific, non-limiting examples, viral diseases include hemorrhagic fever viruses. In some respects, hemorrhagic fever viruses are sand-like viruses, fibrilloviruses, biannviruses, flaviviruses, rhabdoviruses, or combinations thereof. As non-limiting examples, hemorrhagic fever viruses include Ebola virus, Marburg virus, Lassa virus, Junin virus, rotavirus, West Nile virus, Zika virus, Coxsackie virus, hepatitis B virus, Epstein-Barr virus, dengue virus, or Rift Valley virus, etc.

[0158] This document discloses compositions and methods for prophylactically improving viral diseases and their symptoms, such as by administering calcium channel inhibitors like CRAC inhibitors. In some embodiments, a method for improving viral disease symptoms in a person is disclosed. In some embodiments, a method for improving viral disease symptoms in a person is disclosed, comprising the steps of: identifying a person who needs prophylactic improvement of viral disease symptoms; and administering an intracellular calcium signaling inhibitor to the person at a dose sufficient to prophylactically improve the symptoms.

[0159] In some embodiments, common symptoms of viral illness include fever or hemorrhagic diathesis. In further embodiments, symptoms of viral illness include facial flushing, chest flushing, petechiae, capillary leakage, bleeding, swelling, edema, hypotension, shock, or a combination thereof. In still further embodiments, symptoms of viral illness include malaise, muscle pain, headache, vomiting, diarrhea, or a combination thereof.

[0160] 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, improving the symptoms of a viral disease further includes administering an antiviral drug or vaccine.

[0161] In some embodiments, an intracellular calcium signaling inhibitor is delivered to achieve an in vitro IC50 value equal to, approximately equal to, or greater than that measured against the compound. 50 The tissue level concentration is a value. In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which is a value determined in vitro for the compound at an IC50 concentration. 50 Values ​​of 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 40 times, 41 times, 42 times, 43 times, 44 times, 45 times, 46 times, 47 times, 48 ​​times, 49 times, 50 times, 51 times, 52 times, 53 times, 5 4 times, 55 times, 56 times, 57 times, 58 times, 59 times, 60 times, 61 times, 62 times, 63 times, 64 times, 65 times, 66 times, 67 times, 68 times, 69 times, 70 times, 71 times, 72 times, 73 times, 74 times, 75 times, 76 times, 77 times, 78 times, 79 times, 80 times, 81 times, 82 times, 83 times, 84 times, 85 times, 86 times, 87 times, 88 times, 89 times, 90 times, 91 times, 92 times, 93 times, 94 times, 95 times, 96 times, 97 times, 98 times, 99 times, 100 times, or any non-integer multiple in the range of 1 to 100 times.

[0162] In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which is measured in vitro at an IC50 concentration against the compound. 50 The value is within the range of 1 to 100 times, 2 to 80 times, 3 to 60 times, 4 to 50 times, 5 to 45 times, 6 to 44 times, 7 to 43 times, 8 to 43 times, 9 to 41 times, or 10 to 40 times, or any non-integer within the range.

[0163] In some embodiments, calcium signaling inhibitors are delivered to achieve specific tissue 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, and 22 μM. μM, 23μM, 24μM, 25μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 3 6μM, 37μM, 38μM, 39μM, 40μM, 41μM, 42μM, 43μM, 44μM, 45μM, 46μM, 47μM, 48μM, 49μM, 5 0μM, 51μM, 52μM, 53μM, 54μM, 55μM, 56μM, 57μM, 58μM, 59μM, 60μM, 61μM, 62μM, 63μM, 64μM, 65μM, 66μM, 67μM, 68μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, 82μM, 83μM, 84μM, 85μM, 86μM, 87μM, 88μM, 89μM, 90μM, 91μM, 92μM, 93μM, 94μM, 95μM, 96μM, 97μM, 98μM, 99μM, 100μM, or any non-integer in the range of about 1μM to about 100μM.

[0164] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue level concentrations of 1 μM to 100 μM, 2 μM to 90 μM, 3 μM to 80 μM, 4 μM to 70 μM, 5 μM to 60 μM, 6 μM to 50 μM, 7 μM to 40 μM, 8 μM to 30 μM, 9 μM to 20 μM, or 10 μM to 40 μM, or any integer or non-integer concentration within the range.

[0165] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue level concentrations in the range of 9.5 μM to 10.5 μM, 9 μM to 11 μM, 8 μM to 12 μM, 7 μM to 13 μM, 5 μM to 15 μM, 2 μM to 20 μM, or 1 μM to 50 μM, or any integer or non-integer concentration within the range.

[0166] In some embodiments, the method includes preventively improving symptoms of acute viral diseases. In some embodiments, the method includes preventively improving symptoms of chronic viral diseases.

[0167] Preventively improving the symptoms of a viral disease includes reducing the severity, likelihood, or duration of at least one viral disease symptom. This includes reducing the severity, likelihood, or duration of at least one viral disease symptom until said at least one symptom no longer occurs in a person. In some embodiments, preventively improving the symptoms of a viral disease includes reducing the severity, likelihood, or duration of 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 symptoms until, and includes, reducing the severity, likelihood, or duration of all viral disease symptoms (such as those disclosed herein) in a person. In some embodiments, the subject is a non-human mammal instead of a human.

[0168] Calcium signaling and Th17-induced diseases

[0169] T helper cells (Th cells) are essential 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 and are defined by their production of interleukin-17 (IL-17). Abnormal regulation of Th17 is associated with inflammatory diseases and autoimmune diseases. Calcium signaling plays a key role in regulating Th17 differentiation.

[0170] This document discloses compositions and methods for preventively improving Th17-induced diseases and their symptoms, such as by administering calcium channel inhibitors like CRAC inhibitors. In some embodiments, a method for improving symptoms of Th17-induced diseases in humans is disclosed. In some embodiments, a method for improving symptoms of Th17-induced diseases in humans is disclosed, comprising the steps of: identifying a person who needs preventively improved symptoms of Th17-induced diseases; and administering an intracellular calcium signaling inhibitor to the person at a dose sufficient to preventively improve said symptoms.

[0171] In some implementations, symptoms of Th17-induced disease include acute inflammation. Inflammatory symptoms in humans include localized redness, swelling, heat, pain, stiffness, fever, chills, fatigue, headache, loss of appetite, or a combination thereof. In some cases, symptoms occur on the body, including the trunk, arms, hands, fingers, legs, feet, toes, head, neck, bones, joints, throat, sinuses, eyes, or a combination thereof.

[0172] In other implementations, Th17-induced diseases include chronic inflammation or chronic inflammatory diseases. As non-limiting examples, chronic inflammatory diseases include hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, or cancer.

[0173] In a further implementation, Th17-induced diseases include autoimmune diseases. Autoimmune diseases are diseases in which the body's immune system attacks healthy cells. Autoimmune diseases occur in the heart, kidneys, liver, lungs, skin, endocrine glands, exocrine glands, digestive system, tissues, blood, nervous system, or vascular system. As non-limiting examples, autoimmune diseases include rheumatoid arthritis, lupus, celiac disease, psoriasis, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, temporal arteritis, etc.

[0174] 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, improving symptoms of Th17-induced disease further includes administration of an anti-inflammatory drug.

[0175] In some embodiments, an intracellular calcium signaling inhibitor is delivered to achieve an in vitro IC50 value equal to, approximately equal to, or greater than that measured against the compound. 50 The tissue level concentration is a value. In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which is a value determined in vitro for the compound at an IC50 concentration. 50Values ​​of 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 40 times, 41 times, 42 times, 43 times, 44 times, 45 times, 46 times, 47 times, 48 ​​times, 49 times, 50 times, 51 times, 52 times, 53 times, 5 4 times, 55 times, 56 times, 57 times, 58 times, 59 times, 60 times, 61 times, 62 times, 63 times, 64 times, 65 times, 66 times, 67 times, 68 times, 69 times, 70 times, 71 times, 72 times, 73 times, 74 times, 75 times, 76 times, 77 times, 78 times, 79 times, 80 times, 81 times, 82 times, 83 times, 84 times, 85 times, 86 times, 87 times, 88 times, 89 times, 90 times, 91 times, 92 times, 93 times, 94 times, 95 times, 96 times, 97 times, 98 times, 99 times, 100 times, or any non-integer multiple in the range of 1 to 100 times.

[0176] In some embodiments, a calcium signaling inhibitor is delivered to achieve a specific tissue level concentration, which is measured in vitro at an IC50 concentration against the compound. 50 The value is within the range of 1 to 100 times, 2 to 80 times, 3 to 60 times, 4 to 50 times, 5 to 45 times, 6 to 44 times, 7 to 43 times, 8 to 43 times, 9 to 41 times, or 10 to 40 times, or any non-integer within the range.

[0177] In some embodiments, calcium signaling inhibitors are delivered to achieve specific tissue 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, and 22 μM. μM, 23μM, 24μM, 25μM, 26μM, 27μM, 28μM, 29μM, 30μM, 31μM, 32μM, 33μM, 34μM, 35μM, 3 6μM, 37μM, 38μM, 39μM, 40μM, 41μM, 42μM, 43μM, 44μM, 45μM, 46μM, 47μM, 48μM, 49μM, 5 0μM, 51μM, 52μM, 53μM, 54μM, 55μM, 56μM, 57μM, 58μM, 59μM, 60μM, 61μM, 62μM, 63μM, 64μM, 65μM, 66μM, 67μM, 68μM, 69μM, 70μM, 71μM, 72μM, 73μM, 74μM, 75μM, 76μM, 77μM, 78μM, 79μM, 80μM, 81μM, 82μM, 83μM, 84μM, 85μM, 86μM, 87μM, 88μM, 89μM, 90μM, 91μM, 92μM, 93μM, 94μM, 95μM, 96μM, 97μM, 98μM, 99μM, 100μM, or any non-integer in the range of about 1μM to about 100μM.

[0178] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue level concentrations of 1 μM to 100 μM, 2 μM to 90 μM, 3 μM to 80 μM, 4 μM to 70 μM, 5 μM to 60 μM, 6 μM to 50 μM, 7 μM to 40 μM, 8 μM to 30 μM, 9 μM to 20 μM, or 10 μM to 40 μM, or any integer or non-integer concentration within the range.

[0179] In some embodiments, calcium signaling inhibitors are delivered to achieve tissue level concentrations in the range of 9.5 μM to 10.5 μM, 9 μM to 11 μM, 8 μM to 12 μM, 7 μM to 13 μM, 5 μM to 15 μM, 2 μM to 20 μM, or 1 μM to 50 μM, or any integer or non-integer concentration within the range.

[0180] In some embodiments, the method includes preventively improving the symptoms of acute Th17-induced disease. In some embodiments, the method includes preventively improving the symptoms of chronic Th17-induced disease.

[0181] Preventively improving symptoms of Th17-induced disease includes reducing the severity, likelihood, or duration of at least one symptom of Th17-induced disease. Preventively improving symptoms of Th17-induced disease includes reducing the severity, likelihood, or duration of at least one symptom of Th17-induced disease until said at least one symptom no longer occurs in the person. In some embodiments, preventively improving symptoms of Th17-induced disease includes reducing the severity, likelihood, or duration of two, three, four, five, six, seven, eight, nine, or more than nine symptoms of Th17-induced disease until, and includes reducing the severity, likelihood, or duration of all Th17-induced disease symptoms in a person (as disclosed herein). In some embodiments, the subject is a non-human mammal instead of a human.

[0182] certain terms

[0183] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood in relation to the claimed subject matter. Where multiple definitions exist for terms used herein, the definition provided in this section shall prevail. All patents, patent applications, publications, and released nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) cited herein are incorporated by reference. When referring to URLs or other such identifiers or addresses, it should be understood that such identifiers may vary, and specific information on the Internet may vary, but equivalent information can be found by searching the Internet. The accompanying references confirm the availability and public dissemination of such information.

[0184] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only, and are not intended to limit any claimed subject matter. In this specification, unless otherwise expressly stated, the use of the singular includes the plural. It should be noted that, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” as used in this specification and the appended claims include plural indicators. In this application, unless otherwise stated, the use of “or” means “and / or.” Furthermore, the term “comprising” and other forms such as “including” and “comprise” are non-limiting.

[0185] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics discussed.

[0186] Definitions of standard chemical terms can be found in the references, including but not limited to Carey and Sundberg, *Advanced Organic Chemistry, 4th Edition*, Volume A (2000) and Volume B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used.

[0187] Unless explicitly defined, the nomenclature and laboratory procedures and techniques used in connection with analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry as described herein are generally accepted in the art. Standard techniques are used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. Standard techniques are used in recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid transfection). For example, manufacturer-specified kits or reaction and purification techniques as commonly performed in the art or as described herein can be used. The foregoing techniques and procedures are generally performed using conventional methods and as described in the general and more specific references cited and discussed throughout this specification.

[0188] It should be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs, and reagents described herein, and are subject to variation. It should also be understood that the terminology used herein is for the purpose of illustrating specific embodiments only and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0189] The terms “pharmacy kit” and “product” are used as synonyms.

[0190] The terms "subject" or "patient" include both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); farm 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 and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0191] As used herein, the term "treatment" or "manipulation" includes alleviating, reducing, or improving the symptoms of a disease or condition; preventing additional symptoms; improving or preventing the underlying cause of symptoms; suppressing a disease or condition, such as preventing its progression; alleviating a disease or condition; causing a disease or condition to improve; reducing the condition caused by a disease or condition; or preventing and / or therapeutically terminating the symptoms of a disease or condition.

[0192] As used herein, the term "target protein" refers to a protein or protein moiety capable of being bound to or interacting with compounds described herein, such as compounds having a structure from group A of compounds. In some embodiments, the target protein is a STIM protein. In some embodiments, the target protein is an Orai protein.

[0193] As used herein, “STIM protein” includes, but is not limited to, mammalian STIM-1 such as human and rodent (e.g., mouse) STIM-1, D-STIM of Drosophila melanogaster, C-STIM of C. elegans, STIM of Anopheles gambiae, and mammalian STIM-2 such as human and rodent (e.g., mouse) STIM-2. (See paragraphs

[0211] through

[0270] of US 2007 / 0031814 and Table 3 of US 2007 / 0031814, which are incorporated herein by reference). As described herein, such proteins have been identified as involved in, participating in, and / or providing the following functions: calcium pool-manipulated calcium influx or its regulation, cytoplasmic calcium buffering and / or regulation of calcium levels in intracellular calcium pools (e.g., endoplasmic reticulum), or regulation of calcium movement into or out of intracellular calcium pools (e.g., endoplasmic reticulum) or within them.

[0194] 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 nucleotide sequence corresponds to GenBank accession number NM_032790, the Orai2 nucleotide sequence corresponds to GenBank accession number BC069270, and the Orai3 nucleotide sequence corresponds to GenBank accession number NM_152288. As used herein, Orai refers to any Orai gene, such as Orai1, Orai2, or Orai3 (see Table I of WO 07 / 081804). As described herein, these proteins have been identified as involved in, participating in, and / or providing the following functions: calcium influx manipulated by calcium pools or its regulation, cytoplasmic calcium buffering and / or regulation of calcium levels in intracellular calcium pools (e.g., endoplasmic reticulum), or regulation of calcium movement into or out of intracellular calcium pools (e.g., endoplasmic reticulum) or within them.

[0195] When referring to a protein (e.g., STIM, Orai), the term "fragment" or "derivative" means a protein or polypeptide that retains substantially the same biological function or activity as the native protein in at least one assay. For example, the fragment or derivative of the mentioned 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.

[0196] As used herein, improvement of symptoms of a particular disease, condition or symptom by application of a particular compound or pharmaceutical composition means any reduction in severity, delay in onset, slowing of progression or shortening of duration resulting from or related to the application of said compound or composition, whether permanent or temporary, continuous or transient.

[0197] As used herein, the term “regulation” means, directly or indirectly, interacting with a target protein to alter its activity, and by way of example only, includes inhibiting or limiting or reducing the activity of the target.

[0198] As used herein, the term "modifier" refers to a compound that alters the activity of a target. For example, a modifier may cause an increase or decrease in the magnitude of certain activities of a target compared to the activity magnitude in the absence of a modifier. In some embodiments, the modifier is an inhibitor that reduces the magnitude of one or more activities of the target. In some embodiments, the inhibitor completely blocks one or more activities of the target.

[0199] As used herein, “regulation” of intracellular calcium refers to any alteration or adjustment of intracellular calcium, including but not limited to changes in the calcium concentration in the cytoplasm and / or intracellular calcium storage organelles (e.g., the endoplasmic reticulum), and changes in the dynamics of calcium influx into, outflow from, and within the cell. In this respect, regulation means reduction.

[0200] As used herein, the term "target activity" refers to biological activity that can be modulated by a modulator. Some exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and improvement of one or more symptoms associated with a disease or condition.

[0201] As used herein, “inhibition” or “inhibitor” of SOC channel activity or CRAC channel activity refers to the inhibition of calcium channel activity manipulated by calcium pools or calcium channel activity activated by calcium release.

[0202] As used herein, the term "acceptable" in relation to formulations, compositions, or components means that it does not have a lasting adverse effect on the general health of the subject being treated.

[0203] As used herein, the term "pharmaceutically acceptable" means a substance that does not impair the biological activity or properties of a compound and is relatively non-toxic, such as a carrier, diluent, or formulation, which can be administered to an individual without causing unwanted biological effects or interacting in a harmful manner with any component of a composition containing it.

[0204] As used herein, the term "drug combination" refers to a product resulting from the mixing or combination of one or more active ingredients, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that an active ingredient (e.g., a compound having a structure from compound A in the group) and a co-administered agent are administered sequentially to a patient as separate entities, simultaneously, in parallel, or without particular time intervals, wherein the administration provides effective levels of both compounds in the patient. The latter also applies to cocktail therapy, such as the administration of three or more active ingredients.

[0205] The term "pharmaceutical composition" refers to a mixture of a compound having a structure from compound A of this group with other chemical components such as carriers, stabilizers, diluents, surfactants, dispersants, suspending agents, thickeners, and / or excipients. Pharmaceutical compositions facilitate the application of compounds to living organisms. Various techniques exist in the art for administering compounds, including but not limited to: intravenous, oral, aerosol, parenteral, ocular, subcutaneous, intramuscular, pulmonary, and local administration.

[0206] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an amount of drug or compound administered that is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of indications, symptoms, or causes, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic application is the amount of a composition comprising a compound having a structure from compound A of that group required to provide a clinically significant reduction in the symptoms of a disease. The appropriate "effective" amount in any individual case can be determined using techniques such as dose escalation studies.

[0207] As used herein, the term "enhancement" means to increase or prolong the potency or duration of a desired effect. Therefore, in relation to enhancing the potency of a therapeutic agent, the term "enhancement" refers to the ability to increase or prolong the potency or duration of the effect of another therapeutic agent on the system. As used herein, "enhancing effective amount" refers to an amount sufficient to increase the effect of another therapeutic agent on the desired system.

[0208] As used herein, the term "co-administration" means to include the administration of a selected therapeutic agent to a single patient and is intended to include treatment regimens in which the drug is administered via the same or different routes of administration or at the same or different times.

[0209] As used in this article, the term "carrier" refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound into cells or tissues.

[0210] The term "diluent" refers to a chemical compound used to dilute a target compound prior to delivery. Diluents can also be used to stabilize compounds because they provide a more stable environment. Salts dissolved in buffered solutions (which may also provide pH control or maintenance) are used as diluents in the art, including but not limited to phosphate-buffered saline solutions.

[0211] The term "metabolite" of the compounds disclosed herein refers to derivatives of the compounds formed when said compounds are metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, "metabolism" refers to the sum of processes by which an organism alters a particular substance (including, but not limited to, hydrolysis and enzyme-catalyzed reactions). Therefore, enzymes can cause specific structural changes in compounds. For example, cytochrome P450 catalyzes a variety of oxidative and reducing reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, fatty alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from *The Pharmacological Basis of Therapeutics*, 9th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from that host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound.

[0212] "Bioavailability" refers to the percentage by weight of a compound disclosed herein (e.g., a compound from group A) delivered into the total circulation of the studied animal or human. When administered intravenously, total drug exposure (AUC(0-∞)) is generally defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which a compound disclosed herein is absorbed into the total circulation when the pharmaceutical composition is administered orally, compared to intravenous injection.

[0213] "Blood plasma concentration" refers to the concentration of a compound having the structure from compound A in the blood plasma fraction of a subject. It should be understood that the plasma concentration of the compounds described herein may vary significantly among different subjects due to metabolic variability and / or potential interactions with other therapeutic agents. According to one embodiment disclosed herein, the blood plasma concentration of the disclosed compounds may vary among different subjects. Similarly, values ​​such as maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), or area under the plasma concentration-time curve (AUC(0-∞)) may vary among different subjects. Due to this variability, the amount required to constitute a "therapeuticly effective amount" of the compound may vary among different subjects.

[0214] As used in this article, “calcium homeostasis” refers to the overall balance of intracellular calcium levels and movement within the cell, including calcium signaling.

[0215] As used in this article, "intracellular calcium" refers to calcium located within the cell without specifying a particular cellular location. In contrast, calcium in "cytosol" or "cytoplasm" refers to calcium located in the cytoplasm of the cell.

[0216] As used herein, an effect on intracellular calcium is any alteration of any aspect of intracellular calcium, including but not limited to changes in intracellular calcium levels and localization; and calcium influx into or out of the cell or intracellular calcium pools or organelles, or movement therein. For example, an effect on intracellular calcium can be an alteration of the kinetics, sensitivity, rate, amplitude, and electrophysiological properties of calcium influx or movement occurring within the cell or its parts. An effect on intracellular calcium can be an alteration of any intracellular calcium regulatory process, including calcium pool-manipulated calcium influx, cytoplasmic calcium buffering, and calcium levels in or within intracellular calcium pools, or calcium influx into or out of intracellular calcium pools, or movement therein. Any of these aspects can be assessed in a variety of ways, including but not limited to assessing: calcium or other ion (especially cation) levels, calcium or other ion (especially cation) movement, fluctuations in calcium or other ion (especially cation) levels, kinetics of calcium or other ion (especially cation) influx, and / or calcium or other ion (especially cation) transport across membranes. The alteration can be any such change that is statistically significant. Therefore, for example, if it is believed that the intracellular calcium in test cells and control cells is different, then this difference may be statistically significant.

[0217] As used herein, “involved” in relation to the relationship between proteins and intracellular calcium or intracellular calcium regulation means that when the expression or activity of a protein in a cell is reduced, altered, or eliminated, there is an accompanying or associated reduction, alteration, or elimination of one or more aspects of intracellular calcium or intracellular calcium regulation. Such a change or reduction in expression or activity can occur due to alteration in the expression of the gene encoding the protein or by alteration in the protein level. Therefore, proteins involved in aspects of intracellular calcium (e.g., calcium pool-manipulated calcium influx) can be proteins that provide or participate in aspects of intracellular calcium or intracellular calcium regulation. For example, proteins that provide calcium pool-manipulated calcium influx could be STIM proteins and / or Orai proteins.

[0218] The proteins used as components of calcium channels in this article are proteins that participate in the formation of the multi-protein complex of the channel.

[0219] As used herein, the terms "basal" or "resting" for cytosol calcium levels refer to the concentration of calcium in the cytoplasm of a cell, for example, an unstimulated cell that has not been subjected to conditions that would cause calcium to move into, out of, or into the cell. Basal or resting cytosol calcium levels can also be the concentration of free calcium (i.e., calcium not bound to intracellular calcium-binding substances) in the cytoplasm of a cell, for example, an unstimulated cell that has not been subjected to conditions that would cause calcium to move into or out of the cell.

[0220] As used herein, “movement” of ions (including cations such as calcium) refers to the movement or relocation of ions into or outside the cell, or within the cell, such as inflow. Therefore, ion movement can be, for example: movement of ions from the extracellular matrix into the cell, from the cell into the extracellular matrix, from intracellular organelles or storage sites into the cytosol, from the cytosol into intracellular organelles or storage sites, from one intracellular organelle or storage site to another, from the extracellular matrix into intracellular organelles or storage sites, from intracellular organelles or storage sites back to the extracellular matrix, and within the cytoplasm of the cell, from one site to another.

[0221] As used herein, "cation influx" or "calcium influx" into the cell refers to cations, such as calcium, entering intracellular sites, such as the cytoplasm, or entering intracellular organelle cavities or storage sites. Therefore, cation influx can be, for example, the movement of cations from the extracellular matrix or from intracellular organelles or storage sites into the cytoplasm, or the movement of cations from the cytoplasm or extracellular matrix into intracellular organelles or storage sites. The movement of calcium from intracellular organelles or storage sites into the cytoplasm is also referred to as "calcium release" from organelles or storage sites.

[0222] As used herein, “proteins that regulate intracellular calcium” refers to any cellular protein involved in regulating, controlling, and / or altering intracellular calcium. For example, such proteins can participate in altering or regulating intracellular calcium in a variety of ways, including but not limited to: maintaining resting or basal cytoplasmic calcium levels, or participating in cellular responses to signals transmitted within the cell via mechanisms involving deviations in intracellular calcium relative to resting or basal states. In the context of “proteins that regulate intracellular calcium,” “cellular” proteins are cell-related proteins, such as cytoplasmic proteins, plasma membrane-associated proteins, or intracellular membrane proteins. Proteins that regulate intracellular calcium include, but are not limited to, ion-transporting proteins, calcium-binding proteins, and regulatory proteins that regulate ion-transporting proteins.

[0223] As used herein, “improvement” means reducing, preventing, mitigating and / or alleviating the effects of a disease, symptom or condition to achieve improvement of the disease or condition, or at least partial relief of symptoms associated with the disease or condition, up to and including complete reduction such that the effects are zero or practically zero.

[0224] As used herein, “cellular response” refers to any cellular response resulting from the movement of ions into or out of the cell or within the cell. Cellular responses can be associated with any cellular activity that is (at least partially) dependent on ions such as calcium. Such activities can include, for example, cell activation, gene expression, endocytosis, exocytosis, cell transport, and apoptotic cell death.

[0225] As used herein, “immune cells” include cells of the immune system and cells that function or are active in the immune response, such as, but not limited to: T cells, B cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, leukocytes, antigen-presenting cells, and natural killer cells.

[0226] As used in this article, "cytokine" refers to small, soluble proteins secreted by cells that can alter the behavior or properties of the secreting cell or another cell. Cytokines bind to cytokine receptors and trigger intracellular behaviors or properties, such as cell proliferation, death, or differentiation. Exemplary cytokines include, but are not limited to: interleukins (e.g., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-1α, IL-1β, and IL-1RA), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncokinetic protein M, erythropoietin, leukemia suppressor factor (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.

[0227] "Calcium pool-manipulated calcium influx" or "SOCE" refers to a mechanism through which the release of calcium ions from intracellular calcium pools is coordinated with the influx of ions across the plasma membrane.

[0228] "Selective inhibitors of SOC channel activity" refers to inhibitors that are selective for SOC channels while having little effect on the activity of other types of ion channels.

[0229] "Selective inhibitors of CRAC channel activity" refers to inhibitors that are selective for CRAC channels while having minimal effect on the activity of other types of ion channels and / or other SOC channels.

[0230] As used in this article, the term "calcium" can refer to the element or the divalent cation Ca. 2+ .

[0231] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. The scope of the invention is intended to be defined by the following claims, and thereby encompasses the methods and structures within the scope of these claims and their equivalents.

[0232] This invention provides, but is not limited to, the following embodiments:

[0233] 1. A method for improving symptoms of pancreatitis in humans, comprising the following steps:

[0234] Identify individuals who need improvement in pancreatitis symptoms; and

[0235] Intracellular calcium signaling inhibitors were administered to the person at a dose sufficient to improve the symptoms.

[0236] 2. The method as described in Scheme 1, wherein the intracellular calcium signaling inhibitor is a SOC channel inhibitor.

[0237] 3. The method as described in Scheme 1, wherein the intracellular calcium signaling inhibitor is a CRAC channel inhibitor.

[0238] 4. The method of embodiment 1, wherein the intracellular calcium signaling inhibitor inhibits channels containing the STIM1 protein.

[0239] 5. The method of embodiment 1, wherein the intracellular calcium signaling inhibitor inhibits channels containing the Orai1 protein.

[0240] 6. The method of embodiment 1, wherein the intracellular calcium signaling inhibitor inhibits channels containing the Orai2 protein.

[0241] 7. The method of embodiment 1, wherein the intracellular calcium signaling inhibitor is a compound having the following structure: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, N-(4-(1-ethyl-3-(thiazo-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoro)...) 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) N-((3-methylisothiazolyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxane-hexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyrazol Pyridine-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazolyl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-Difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0242] 8. The method as described in any one of embodiments 1-7, wherein the symptoms are symptoms of acute pancreatitis.

[0243] 9. The method according to any one of embodiments 1-7, wherein the symptoms include at least one of the following: pancreatic inflammation and edema, upper abdominal pain radiating to the back, pain in the left upper quadrant radiating to the back, nausea, vomiting, vomiting that worsens with eating, increased heart rate, tachycardia, increased respiratory rate, increased blood pressure, decreased blood pressure, dehydration, abdominal tenderness, fever, chills, peritonitis, hemodynamic instability, and reflex paralysis.

[0244] 10. The method as described in any one of embodiments 1-7, wherein the symptoms are severe acute pancreatitis symptoms.

[0245] 11. The method of any one of embodiments 1-7, wherein the symptoms include at least one of pancreatic necrosis and extrapancreatic organ injury.

[0246] 12. The method as described in any one of embodiments 1-7, wherein the symptoms are symptoms of chronic pancreatitis.

[0247] 13. The method according to any one of embodiments 1-7, wherein the symptoms include at least one of the following: persistent abdominal pain, digestive defects, malabsorption of fat, pain during food intake, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP inflammatory markers, impaired bicarbonate production, elevated fecal elastase levels, elevated serum trypsinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels.

[0248] 14. The method of any one of embodiments 1-7, wherein the symptoms include at least one of the following: elevated ESR level, elevated IgG4 level, elevated rheumatoid factor, presence of ANA antibody and presence of anti-smooth muscle antibody.

[0249] 15. The method of any one of embodiments 1-7, wherein the symptoms include at least one of the following: steatorrhea, Sudan chemical staining of feces or 7 g or more of fecal fat excretion within 24 hours after a 100 g fat diet, and a fecal elastase value of less than 200 μg / g in the fecal sample.

[0250] 16. The method according to any one of embodiments 1-12, wherein the symptoms include at least one of the following: abdominal pain, elevated blood amylase level, elevated blood lipase level, enlarged pancreas, nausea, vomiting, internal bleeding, paralytic ileus, fever, jaundice, weight loss, and increased heart rate.

[0251] 17. The method of any one of embodiments 1-12, wherein the symptoms include elevated serum amylase levels.

[0252] 18. The method as described in any one of embodiments 1-12, wherein the symptoms include elevated serum lipase levels.

[0253] 19. The method as described in any one of embodiments 1-12, wherein the symptoms include necrosis detected by computed tomography (CT) scan.

[0254] 20. The method of any one of embodiments 1-12, wherein the symptoms include premature activation of digestive enzymes.

[0255] 21. The method of embodiment 20, wherein the premature activation of the digestive enzyme occurs in the pancreas of the person.

[0256] 22. The method of embodiment 20, wherein the enzyme comprises trypsin.

[0257] 23. A method for preventing or improving symptoms associated with pancreatic disease in persons at risk of pancreatic disease, comprising the following steps:

[0258] Identify individuals with risk factors associated with pancreatic disorders; and

[0259] Intracellular calcium signaling inhibitors should be administered at a dose sufficient to prevent or mitigate the aforementioned side effects.

[0260] 24. The method of embodiment 23, wherein the intracellular calcium inhibitor is a SOC channel inhibitor.

[0261] 25. The method of embodiment 23, wherein the intracellular calcium inhibitor is a CRAC channel inhibitor.

[0262] 26. The method of embodiment 23, wherein the intracellular calcium signaling inhibitor is a compound having the following structure: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(4-(1-ethyl-3-(thiazo-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1-methyl-1H-pyrazol-5-carboxamide, 3-fluoro-4-(1- Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxane-hexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyrazol Pyridine-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazolyl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-Difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0263] 27. The method of embodiment 23, wherein the intracellular calcium signaling inhibitor is a compound with the chemical name 2,6-difluoro-N-(1-(4-hydroxy-2-(trifluoromethyl)benzyl)-1H-pyrazol-3-yl)benzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

[0264] 28. The method as described in any one of embodiments 23-27, wherein the pancreatic symptoms include symptoms of acute pancreatitis.

[0265] 29. The method as described in any one of embodiments 23-27, wherein the pancreatic condition includes symptoms of chronic pancreatitis.

[0266] 30. The method of any one of embodiments 23-29, wherein the person suffers from pancreatitis due to undergoing a drug regimen comprising administration of at least one of the following: steroids such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone, and olanzapine.

[0267] 31. The method of any one of embodiments 23-29, wherein the person is identified as carrying a genetic form of pancreatitis.

[0268] 32. The method of embodiment 31, wherein the person carries at least one of the following alleles: trypsin 1 encoding trypsinogen, SPINK1 encoding trypsin inhibitor, and cystic fibrosis transmembrane transport regulator.

[0269] 33. The method of any one of embodiments 23-29, wherein the person suffers from pancreatitis due to at least one of the following: hypercalcemia, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic rupture, congenital pancreatic malformation, type 2 diabetes, pancreatic cancer, pancreatic duct stones, vasculitis, pancreatic small vessel inflammation, Coxsackie virus infection, and porphyria, such as acute intermittent porphyria and erythropoietic protoporphyria.

[0270] 34. The method as described in any one of embodiments 23-29, wherein the physical health of the person has been affected by at least one of the following: gallstones, alcohol poisoning, alcohol poisoning, trauma, mumps, autoimmune disease, scorpion sting, hyperlipidemia, hypothermia, hyperparathyroidism, endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid.

[0271] 35. The method of any one of embodiments 23-29, wherein the physical health of the person has been affected by at least one of the following: cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps virus, varicella-zoster virus, Legionella bacteria, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungi, Ascaris parasites, Cryptosporidium cells, and Toxoplasma cells.

[0272] 36. A composition comprising an intracellular calcium signaling inhibitor and at least one drug associated with negative effects on pancreatic activity.

[0273] 37. The composition of embodiment 36, wherein the drug is selected from: steroids such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone and olanzapine, azathioprine and valproic acid.

[0274] 38. The composition of embodiment 36, wherein the intracellular calcium signaling inhibitor is a SOC inhibitor.

[0275] 39. The composition of embodiment 36, wherein the intracellular calcium signaling inhibitor is a CRAC inhibitor.

[0276] 40. The composition according to any one of embodiments 36-39, wherein the intracellular calcium signaling inhibitor is a compound having the following structure: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(4-(1-ethyl-3-(thiazo-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1 -Methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazol-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxane-hexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl)-1H-pyrazol-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]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazolyl)-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-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0277] 41. A dosing regimen comprising administering to an individual a drug associated with a negative effect on pancreatic activity, and administering an intracellular calcium signaling inhibitor.

[0278] 42. The dosing regimen as described in embodiment 41, wherein the drug is selected from steroids such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone and olanzapine, azathioprine and valproic acid.

[0279] 43. The dosing regimen as described in embodiment 41, wherein the intracellular calcium signaling inhibitor is a SOC inhibitor.

[0280] 44. The dosing regimen as described in embodiment 41, wherein the intracellular calcium signaling inhibitor is a CRAC inhibitor.

[0281] 45. The dosing regimen of embodiment 41, wherein the intracellular calcium signaling inhibitor is a compound having the following structure: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(4-(1-ethyl-3-(thiazo-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N -(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazol-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)- 1-Methyl-1H-pyrazole-5-carboxamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)-N-((3-methylisothiazolyl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxanehexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl)-1H-pyrazole-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl)-1H-pyrazole-4-yl)phenyl)isonicotinamide, 5-(1- Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazolyl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-Trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0282] 46. ​​A composition for improving symptoms of pancreatitis in humans, the improvement comprising the following steps:

[0283] Identify individuals who need improvement in pancreatitis symptoms; and

[0284] Intracellular calcium signaling inhibitors were administered to the person at a dose sufficient to improve the symptoms.

[0285] 47. The composition used as described in embodiment 46, wherein the intracellular calcium signaling inhibitor is a SOC channel inhibitor.

[0286] 48. The composition used as described in embodiment 46, wherein the intracellular calcium signaling inhibitor is a CRAC channel inhibitor.

[0287] 49. The composition used as described in embodiment 46, wherein the intracellular calcium signaling inhibitor inhibits channels containing the STIM1 protein.

[0288] 50. The composition used as described in embodiment 46, wherein the intracellular calcium signaling inhibitor inhibits channels containing the Orai1 protein.

[0289] 51. The composition used as described in embodiment 46, wherein the intracellular calcium signaling inhibitor inhibits channels containing the Orai2 protein.

[0290] 52. The composition used as described in Embodiment 46, wherein the intracellular calcium signaling inhibitor is a compound having the following structure: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(4-(1-ethyl-3-(thiazo-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl- N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazol-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)- 1-Methyl-1H-pyrazole-5-carboxamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)-N-((3-methylisothiazolyl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxanehexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl)-1H-pyrazole-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl)-1H-pyrazole-4-yl)phenyl)isonicotinamide, 5-(1- Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazolyl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-Trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0291] 53. The composition used as described in any of embodiments 46 further comprises an analgesic drug.

[0292] 54. The composition used as described in embodiment 53, wherein the analgesic includes opium tablets.

[0293] 55. The composition used as described in embodiment 53, wherein the analgesic includes morphine.

[0294] 56. The composition used as described in any one of embodiments 46-55, wherein the symptoms are symptoms of acute pancreatitis.

[0295] 57. The composition used as described in any one of embodiments 46-56, wherein the symptoms include at least one of the following: pancreatic inflammation and edema, upper abdominal pain radiating to the back, pain in the left upper quadrant of the back radiating to the back, nausea, vomiting, vomiting that worsens with eating, increased heart rate, tachycardia, increased respiratory rate, increased blood pressure, decreased blood pressure, dehydration, abdominal tenderness, fever, chills, peritonitis, hemodynamic instability, and reflex paralysis.

[0296] 58. The composition used as described in any one of embodiments 46-55, wherein the symptoms are severe pancreatitis symptoms.

[0297] 59. The composition used as described in any one of embodiments 46-55, wherein the symptoms include at least one of pancreatic necrosis and extrapancreatic organ injury.

[0298] 60. The composition used as described in any one of embodiments 46-55, wherein the symptoms are symptoms of chronic pancreatitis.

[0299] 61. The composition used as described in any one of embodiments 46-55, wherein the symptoms include at least one of the following: persistent abdominal pain, digestive defects, malabsorption of fat, pain during food intake, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP inflammatory markers, impaired bicarbonate production, elevated fecal elastase levels, elevated serum trypsinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels.

[0300] 62. The composition used as described in any one of embodiments 46-55, wherein the symptoms include at least one of the following: elevated ESR level, elevated IgG4 level, elevated rheumatoid factor, presence of ANA antibody, presence of anti-smooth muscle antibody, the determination of any one of which can indicate chronic pancreatitis in a person.

[0301] 63. The composition used as described in any one of embodiments 46-55, wherein the symptoms include at least one of the following: steatorrhea, Sudan chemical staining of feces or 7 g or more of fecal fat excretion within 24 hours after a 100 g fat diet, and a fecal elastase value of less than 200 μg / g in the fecal sample.

[0302] 64. The composition used as described in any one of embodiments 46-55, wherein the symptoms include at least one of the following: abdominal pain, elevated blood amylase levels, elevated blood lipase levels, enlarged pancreas, nausea, vomiting, internal bleeding, paralytic ileus, fever, jaundice, weight loss, and increased heart rate.

[0303] 65. The composition used as described in any one of embodiments 46-55, wherein the symptoms include premature activation of digestive enzymes.

[0304] 66. The composition used as described in embodiment 65, wherein the premature activation of the digestive enzyme occurs in the pancreas of the person.

[0305] 67. The composition used as described in embodiment 65, wherein the enzyme comprises trypsin.

[0306] 68. A composition for preventing or improving pancreatic disease-related symptoms in persons at risk of pancreatic disease, the prevention or improvement comprising the steps of:

[0307] Identify individuals with risk factors associated with pancreatic disorders; and

[0308] Intracellular calcium signaling inhibitors should be administered at a dose sufficient to prevent or mitigate the aforementioned side effects.

[0309] 69. The composition used as described in embodiment 68, wherein the intracellular calcium inhibitor is a SOC channel inhibitor.

[0310] 70. The composition used as described in embodiment 68, wherein the intracellular calcium inhibitor is a CRAC channel inhibitor.

[0311] 71. The composition used as described in Embodiment 68, wherein the intracellular calcium signaling inhibitor is a compound having the following structure: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(4-(1-ethyl-3-(thiazo-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl- N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazol-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)- 1-Methyl-1H-pyrazole-5-carboxamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)-N-((3-methylisothiazolyl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxanehexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl)-1H-pyrazole-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl)-1H-pyrazole-4-yl)phenyl)isonicotinamide, 5-(1- Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazolyl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-Trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0312] 72. The composition used as described in any of embodiments 68, wherein the pancreatic condition includes symptoms of acute pancreatitis.

[0313] 73. The composition used as described in any one of embodiments 68-72, wherein the pancreatic condition includes symptoms of chronic pancreatitis.

[0314] 74. The composition used as described in any one of embodiments 68-73, wherein the person undergoes a pharmaceutical regimen comprising administration of at least one of the following: steroids such as corticosteroids, prednisolone, HIV drugs, norinosine, pentazocine, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins such as cholesterol-lowering statins, antiglycemic agents, metformin, gliptins such as vildagliptin and sitagliptin, atypical antipsychotics, clozapine, risperidone, and olanzapine.

[0315] 75. The composition used as described in any one of embodiments 68-73, wherein the person is identified as carrying a genetic form of pancreatitis.

[0316] 76. The composition used as described in embodiment 75, wherein the person carries a mutant allele of at least one of the following: trypsin 1 encoding trypsinogen, SPINK1 encoding trypsin inhibitor, and cystic fibrosis transmembrane transport regulator.

[0317] 77. The composition used as described in any one of embodiments 68-73, wherein the person suffers from at least one of the following: hypercalcemia, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic dysplasia, congenital pancreatic malformation, type 2 diabetes, pancreatic cancer, pancreatic duct stones, vasculitis, pancreatic small vessel inflammation, Coxsackie virus infection, and porphyria, such as acute intermittent porphyria and erythropoietic protoporphyria.

[0318] 78. The composition used as described in any one of embodiments 68-73, wherein the person's health condition has been affected by at least one of the following: gallstones, alcohol poisoning, alcohol poisoning, trauma, mumps, autoimmune disease, scorpion sting, hyperlipidemia, hypothermia, hyperparathyroidism, endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid.

[0319] 79. The composition used as described in any one of embodiments 68-73, wherein the person's health condition has been affected by at least one of the following: cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella bacteria, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungi, Ascaris parasites, Cryptosporidium cells, and Toxoplasma cells.

[0320] 80. A method for improving symptoms of viral infection in humans, comprising the following steps:

[0321] Identify individuals who need improvement in their viral infection symptoms; and

[0322] Intracellular calcium signaling inhibitors were administered to the person at a dose sufficient to improve the symptoms.

[0323] 81. The method of embodiment 80, wherein the intracellular calcium signaling inhibitor is a SOC channel inhibitor.

[0324] 82. The method of embodiment 80, wherein the intracellular calcium signaling inhibitor is a CRAC channel inhibitor.

[0325] 83. The method of embodiment 80, wherein the intracellular calcium signaling inhibitor inhibits channels containing the STIM1 protein.

[0326] 84. The method of embodiment 80, wherein the intracellular calcium signaling inhibitor inhibits channels containing the Orai1 protein.

[0327] 85. The method of embodiment 80, wherein the intracellular calcium signaling inhibitor inhibits channels containing the Orai2 protein.

[0328] 86. The method of embodiment 80, wherein the intracellular calcium signaling inhibitor is a compound having the following structure: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(4-(1-ethyl-3-(thiazo-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1-methyl-1H-pyrazol-5-carboxamide, 3-fluoro-4-(1- Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxane-hexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyrazol Pyridine-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazolyl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-Difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0329] 87. The method of embodiment 80, wherein the viral infection is a hemorrhagic fever virus.

[0330] 88. The method as described in any one of embodiments 80-87, wherein the symptoms are hemorrhagic fever virus symptoms.

[0331] 89. The method as described in any one of embodiments 80-87, wherein the symptoms include at least one of the following: fever, hemorrhagic diathesis, facial flushing, chest flushing, petechiae, capillary leakage, bleeding, swelling, edema, hypotension, shock, malaise, muscle pain, headache, vomiting, and diarrhea.

[0332] 90. The method as described in any one of embodiments 80-87, wherein the symptoms include elevated levels of cellular virus.

[0333] 91. A method for improving symptoms of Th17-induced disease in humans, comprising the following steps:

[0334] Identify individuals who require improvement of symptoms in Th17-induced diseases; and

[0335] Intracellular calcium signaling inhibitors were administered to the person at a dose sufficient to improve the symptoms.

[0336] 92. The method of embodiment 91, wherein the intracellular calcium signaling inhibitor is a SOC channel inhibitor.

[0337] 93. The method of embodiment 91, wherein the intracellular calcium signaling inhibitor is a CRAC channel inhibitor.

[0338] 94. The method of embodiment 91, wherein the intracellular calcium signaling inhibitor inhibits channels containing the STIM1 protein.

[0339] 95. The method of embodiment 91, wherein the intracellular calcium signaling inhibitor inhibits channels containing the Orai1 protein.

[0340] 96. The method of embodiment 91, wherein the intracellular calcium signaling inhibitor inhibits channels containing the Orai2 protein.

[0341] 97. The method of embodiment 91, wherein the intracellular calcium signaling inhibitor is a compound having the following structure: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(4-(1-ethyl-3-(thiazo-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1-methyl-1H-pyrazol-5-carboxamide, 3-fluoro-4-(1- Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxane-hexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyrazol Pyridine-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazolyl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-Difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof.

[0342] 98. The method as described in any one of embodiments 91-97, wherein the symptoms are acute inflammatory symptoms.

[0343] 99. The method as described in any one of embodiments 91-97, wherein the symptoms include at least one of the following: redness, swelling, heat, pain, stiffness, fever, chills, fatigue, headache, and loss of appetite.

[0344] 100. The method of embodiment 99, wherein the patient’s symptoms occur in the trunk, arms, hands, fingers, legs, feet, toes, head, neck, bones, joints, throat, sinuses, eyes, or a combination thereof.

[0345] 101. The method as described in any one of embodiments 91-97, wherein the Th17-induced disease is an inflammatory disease.

[0346] 102. The method of embodiment 101, wherein the inflammatory disease includes hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, or cancer.

[0347] 103. The method as described in any one of embodiments 91-97, wherein the Th17-induced disease is an autoimmune disease.

[0348] 104. The method of embodiment 103, wherein the autoimmune disease includes rheumatoid arthritis, lupus, celiac disease, psoriasis, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, or temporal arteritis.

[0349] 105. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in Embodiment 7 and a pharmaceutically acceptable excipient.

[0350] 106. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in embodiment 23 and a pharmaceutically acceptable excipient.

[0351] 107. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in embodiment 40 and a pharmaceutically acceptable excipient.

[0352] 108. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in embodiment 45 and a pharmaceutically acceptable excipient.

[0353] 109. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in embodiment 52 and a pharmaceutically acceptable excipient.

[0354] 110. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in embodiment 71 and a pharmaceutically acceptable excipient.

[0355] 111. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in embodiment 86 and a pharmaceutically acceptable excipient.

[0356] 112. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in embodiment 97 and a pharmaceutically acceptable excipient.

[0357] Example

[0358] Example 1: GSK-7975A-induced CRAC channel inhibition blocks necrosis of pancreatic acinar cells in mice and humans.

[0359] Mouse pancreatic acinar cells (PACs) were extracted and incubated with a vector (control) or with natural bile acid TLCS (taurolcite 3-sulfate) in the absence or presence of GSK-7975A. Cells were contacted with propidium iodide to determine cell necrosis. In vitro treatment of individual cells with TLCSs simulated the effect of gallstones or other obstructions on pancreatic secretion in vivo.

[0360] like Figure 1A As shown, TLCS induced approximately 45% cell necrosis during the experiment. The addition of 10 μM GSK-7975A reduced this percentage of necrosis by half, to approximately 23%. An asterisk indicates a statistically significant change. Cells not treated with TLCS showed approximately 10% necrosis. These results demonstrate that GSK-7975A reduces the necrosis-inducing effect of TLCS on mouse PACs.

[0361] Human PACs were extracted and incubated with a vector (control) or with natural bile acid TLCS in the absence or presence of GSK-7975A. Cells were contacted with propidium iodide to determine cell necrosis. In vitro treatment of individual cells with TLCS simulated the effect of gallstones or other obstructions on pancreatic secretion in vivo.

[0362] like Figure 1BAs shown, TLCS induced approximately 45% cell necrosis during the experiment. The addition of 10 μM GSK-7975A reduced this percentage of necrosis to approximately 30%. An asterisk indicates a statistically significant change. Cells not treated with TLCS showed approximately 23% necrosis. These results demonstrate that GSK-7975A reduces the necrosis-inducing effect of TLCS on human PACs.

[0363] Example 2: Histopathological changes in a mouse AP model by blocking CRAC channel inhibitor (GSK-7975A)

[0364] The effects of CRAC inhibitors on pancreatic histopathological progression were evaluated using a mouse model of acute pancreatitis. CCK receptors in the normal calcium signaling pathway of the mouse pancreas were overstimulated with taenin. Acute pancreatitis was induced by TLCS by mimicking excessive bile acids (as experienced in gallstone-induced acute pancreatitis). Alcohol-induced acute pancreatitis was mimicked using fatty acid ethyl esters (FAEE). Acute pancreatitis agents (taenin, ...) alone were used. Figure 2A ;TLCS, Figure 2B ; or FAEE, Figure 2C Mice were treated with CRAC inhibitor GSK-7975A (using the CRAC inhibitor IC50). 50 Mice were treated with 10 or 40 times the concentration of the drug.

[0365] It was observed that GSK-7975A significantly reduced the overall histopathological score in mice treated with this agent compared to mice treated without CRAC inhibitors. This effect was statistically significant and showed an IC50 value of 40-fold. 50 The time ratio is 10 times IC 50 The effect was more significant at lower concentrations, but was also observed at lower concentrations. An asterisk indicates a statistically significant change. [The text then abruptly shifts to a seemingly unrelated topic:] ...reaching its in vitro IC50... 50 At tissue-level doses of 10 or 40 times the value, GSK-7975A produced a significant reduction in pancreatic histopathology.

[0366] Figure 2A , 2B The results shown in 2C indicate that CRAC inhibitors can improve the histopathological symptoms of acute pancreatitis. This effect was observed regardless of the inducer or the type of acute pancreatitis being modeled.

[0367] Example 3: Compound I and GSK-7975A inhibit CRAC channels

[0368] The inhibitory effects of compound I and GSK-7975A on CRAC channels were determined. Channels containing Orai1 / STIM1 and Orai2 / STIM1 were also measured. Figure 3A As shown, the average IC50 value of compound I was determined to be 119 nM. 50Suppress the Orai1 / STIM1 channel, with an average IC50 of 895 nm. 50 Suppress the Orai2 / STIM1 channels. For example... Figure 3B As shown, the average IC of GSK-7975A was determined to be 398nM. 50 Suppress the Orai1 / STIM1 channel, with an average IC50 of 1453 nm. 50 Inhibition of Orai2 / STIM1 channels. Compared to GSK-7975A, compound I is approximately 4 times more potent against Orai1-type CRAC channels. Both compounds are more effective against Orai1-type CRAC channels than against Orai2-type CRAC channels.

[0369] These results suggest that the observed effects of GSK-7975A on calcium signaling can be extrapolated to CRAC inhibitors, and that CRAC inhibitors other than GSK-7975A may be superior to GSK-7975A in certain parameters.

[0370] Example 4: Compound I blocks calcium pooling in mouse pancreatic acinar cells. 2+ Internal flow (SOCE)

[0371] Mouse pica cells were isolated and the effect of CRAC inhibitors on calcium reuptake in the ER was determined. Cells were treated with cyclopiranic acid (CPA) alone. Figure 4A ) or combine it with CRAC inhibitor compound I ( Figure 4B Treating cells to activate CRAC channels, thereby releasing Ca2+. 2+ Fifteen minutes after calcium release, excess calcium was provided to the cells, and calcium uptake into the ER was monitored. Cells treated with the CRAC inhibitor did not show calcium reuptake.

[0372] These results indicate that CRAC inhibitors can block the ability of cells to reload their ER with calcium for successive rounds of signal transduction.

[0373] Example 5: Compound I and GSK-7975A blocked SOCE in mouse pancreatic acinar cells in a dose-dependent manner.

[0374] Using CRAC inhibitor compound I ( Figure 5A ) or GSK-7975A ( Figure 5B Mice were treated with PAC and their calcium uptake rates were monitored. After treatment with 700 nM inhibitors, both CRAC inhibitors reduced the rate of manipulated calcium influx into the calcium pool in the ER to 50% of the control level. At 10 mM, compound I blocked 100% of reuptake.

[0375] This example demonstrates that multiple CRAC inhibitors each inhibit SOCE in mammalian PACs.

[0376] Example 6: Compound I Blocking CKK-induced Ca in mouse pancreatic acinar cells 2+ internal flow

[0377] Calcium uptake in mouse PACs was monitored after treatment with 10 nM CCK. Cells were treated with CCK, then given 1.8 mM calcium, and calcium reuptake was monitored. It was observed that cells pretreated with a CRAC inhibitor ( Figure 6B ) and untreated cells ( Figure 6A Compared to the control, it showed a significant reduction in calcium reuptake. Pretreatment with compound I reduced calcium reuptake to near 0%. GSK-7975A reduced calcium reuptake to approximately 30% of the control.

[0378] These results indicate that CRAC inhibitors can effectively reduce the overactive calcium signaling in PAC.

[0379] Example 7: Compound I inhibits multiple cytokines

[0380] The inhibitory effects of compound I on various cytokines were tested. The inhibitory effects of the CRAC inhibitor compound I were tested against cytokines INF-γ, IL-4, and IL-4 expressed on acinar cells, cytokines IL-1β, IL-6, IL-10, and TNF-α expressed on acinar cells, and cytokines IL-2 and IL-7, which are important in T cell function. T cells in whole human PBMCs were stimulated for 48 hours in buffer + 10% serum with plate-bound anti-CD3 / anti-CD28. Released cytokines were measured using a Millipore Luminex. Results are shown in… Figure 7 In human PBMCs, compound I strongly inhibited the release of multiple cytokines that play important roles in T cells.

[0381] These cytokine data, together with the PAC data, support the conclusion that compound I has a dual role in acute pancreatitis—inhibiting immune cell and pancreatic acinar cell signaling pathways and cell death.

[0382] Example 8: Compound I showed stability in a mouse calcinurin model of acute pancreatitis. Certain effects

[0383] Mice were prophylactically treated with a CRAC inhibitor or mediator, followed by CCK stimulation to induce acute pancreatitis. Prophylactic intraperitoneal administration of compound I significantly and dose-dependently reduced the production of serotonin-induced pathology in the mouse pancreas (C57B6 mice). This effect was significantly lower than the positive control CsA at 5 mg / kg and increased in a dose-dependent manner. See also Figure 8A This treatment showed that, following intraperitoneal injection, the level of compound I in the pancreas increased proportionally to the dose (see [link to treatment]). Figure 8B This is consistent with the above. Figure 8A The positive results correspond to those in the data.

[0384] These results suggest that administration of CRAC prior to or concurrently with a second drug suspected of triggering or increasing the risk of acute pancreatitis can preventively avoid or reduce the risk of acute pancreatitis.

[0385] Example 9: Compound I reduced serum amylase and serum lipids in a mouse model of acute pancreatitis induced by frog dermatin. enzyme levels

[0386] Mice were untreated (normal), treated with CCK alone (the medium), or treated with CCK in combination with CsA or CRAC inhibitors at a specified dose. Serum amylase activity was measured. Figure 9A ) and serum lipase activity ( Figure 9B (IU / L).

[0387] The CRAC inhibitor compound I performed as well as or better than the positive control CsA at a maximum concentration of 20 mg / kg. Compound I caused a significant and dose-dependent decrease in dermalin-induced serum amylase and serum lipase activities.

[0388] Example 10: Compound I reduces pancreatic pathology in a therapeutic mouse model of frog dermatitis.

[0389] Pancreatitis was induced by seven intraperitoneal injections of scutellarin, administered hourly, with animals sacrificed eight hours after the first injection. Compound I was administered intraperitoneally 30 minutes before the first scutellarin injection (prophylactic) or after the third injection (therapeutic). CsA was administered orally following the same protocol as Compound I. Results were... Figure 10 As shown in the image.

[0390] Histopathological scores were measured based on observations of acinar cell degeneration and coagulative necrosis, as well as measurements of inflammation and edema. When administered after the third injection of taenin, compound I resulted in a significant 35% reduction in taenin-induced pathology in the pancreas, consistent with efficacy in the treatment modality. Prophylactic treatment with compound I also reduced pathology by 26%.

[0391] The results showed that CRAC inhibitors, such as compound I, had a significant impact on pancreatic histopathological scores when administered prophylactically or therapeutically.

[0392] Example 11: Compound I blocks TLCS-induced Ca2+ in mouse pancreatic acinar cells 2+ internal flow

[0393] Mouse pacillar cells (PACs) were treated with 500 μM TLCS and 0 μM, 1 μM, or 3 μM of CRAC inhibitor compound I. Cytosol calcium levels were measured for each treatment (as an F345 / F380 ratio). TLCS reduced calcium levels in mice. 2+ Release from the intracellular calcium pool (not shown) triggers SOCE. In this experiment, 1 or 3 μM of compound I completely blocked TLCS-induced calcium release. 2+ Inflow. The result was... Figure 11As shown in the image.

[0394] These results indicate that CRAC inhibitors can effectively and positively affect calcium signaling in gallstone-associated acute pancreatitis in mammals.

[0395] Example 12: Compound I and other CCIs inhibit TLCS-induced amylase release from mouse pancreatic acinar cells

[0396] Amylase release from PACs exhibits both ER-dependent and CRAC / cytosol-dependent components. This calcium-dependent component is blocked by the introduction of the divalent cationic chelator EGTA. Mouse acinar cells were treated with TLCS and a mediator, EGTA, or a CRAC inhibitor such as compound I, GSK-7975A, or compound II, and amylase release was monitored. CRAC inhibitors were observed to mimic EGTA in their effect on amylase release. See also Figure 12 .

[0397] These results indicate that CRAC inhibitors block the reuptake of calcium into the ER following TLCS-induced calcium release, thus mimicking the effect of EGTA on amylase release inhibition.

[0398] Example 13: Compound I inhibits TLCS-induced necrosis in mouse pancreatic acinar cells

[0399] Mouse plastin cells (PACs) were treated with DMSO, DMSO plus 500 μM TLCS, or DMSO plus 500 μM TLCS plus 1 μM CRAC inhibitor compound I. Cell necrosis was measured as a percentage of PI uptake. CRAC inhibitor compound I inhibited TLCS-induced necrosis in mouse PACs.

[0400] These data and Ca 2+ Together with amylase data, this indicates that compound I is effective in the TLCS model of AP.

[0401] Example 14: Safety and efficacy of compound I, GSK-7975A and compound II in patients with acute pancreatitis Phase II clinical trial

[0402] The purpose of this phase II trial is to investigate the safety, tolerability, pharmacokinetic (PK), PD, and efficacy of single and repeated intravenous infusions of calcium signaling inhibitors such as compound I, GSK-7975A, and compound II, or compounds selected from compound A of this group, in patients with acute pancreatitis and SIRS.

[0403] patient This study recruited 30 patients at high risk of developing moderate or severe pancreatitis, as assessed based on a SIRS score of 2 or higher at the time of enrollment.

[0404] standard :

[0405] Selection criteria :

[0406] • All participants must use acceptable contraception to ensure that no pregnancy occurs during the study and for at least 12 weeks after administration to men and 32 weeks after administration to women;

[0407] In addition to the weight range of 55-95kg, the body mass index is also between 18.5-35kg / m². 2 Within the range (including endpoints);

[0408] • Participants must be able to provide informed consent and comply with research requirements and schedules;

[0409] • Male and female subjects aged 18 or older are eligible.

[0410] • Subjects must experience their first acute pancreatitis attack in their lifetime.

[0411] • The diagnosis of acute pancreatitis must be based on two of the following three criteria: (1) typical upper abdominal pain; (2) serum amylase and / or lipase elevated to at least three times the upper limit of normal; (3) contrast-enhanced CT scan or abdominal ultrasound showing changes in acute pancreatitis.

[0412] • Subjects must demonstrate a history of alcoholism, hypertriglyceridemia, or biliary tract etiology (for biliary pancreatitis, ultrasound must exclude stone obstruction at the time of study screening) that supports a current episode of pancreatitis.

[0413] • Subjects must show a BISAP score of 3 or higher.

[0414] Treatment studies may begin within 48 hours of symptom onset.

[0415] Exclusion criteria:

[0416] • The likelihood of invasive biliary intervention (such as ERCP) is high in the following week. • Recurrent pancreatitis.

[0417] • CT evidence of pancreatic necrosis upon entry into the study.

[0418] • Severe chronic renal failure (modified renal diet formula 30mL / min or dependent on renal dialysis).

[0419] • New York Heart Association heart failure of grade II or higher.

[0420] • Oxygen-dependent chronic obstructive pulmonary disease (COPD).

[0421] • Cirrhosis of the liver.

[0422] • Severe anemia (hemoglobin less than 8g / dL).

[0423] • At the time of entry into the study, the hematocrit is below 35% or above 45% (fluid may be administered to correct the hematocrit before randomization, provided that the study treatment begins within 48 hours of symptom onset).

[0424] • At the start of the study, serum alanine aminotransferase levels were above 250 IU / L.

[0425] • Upon entry into the study, ascending cholangitis was clinically suspected.

[0426] • Active gastrointestinal bleeding.

[0427] • Currently, the malignant tumor is not in remission (except for basal cell carcinoma of the skin).

[0428] • Change in mental state.

[0429] • Currently breastfeeding or pregnant.

[0430] • Women of childbearing age who are unwilling to adopt appropriate and effective birth control measures (less than 2 years postmenopausal or who have not undergone surgical sterilization).

[0431] • Known hypersensitivity to any component of the product used in the study.

[0432] • Having a dependency relationship with researchers or sponsors.

[0433] • Participate in the investigational drug study during the clinical trial or within 30 days prior to the start of the clinical trial.

[0434] Research Design This study was a randomized, double-blind, placebo-controlled, multicenter, multinational, parallel-group study that compared the placebo group with a CRAC inhibitor group receiving intravenous CRAC inhibitor treatment twice daily for up to 7 consecutive days.

[0435] The study recruited 45 patients who were at high risk of developing moderate or severe pancreatitis, as assessed based on an SIRS score of 2 or higher at the time of enrollment.

[0436] The primary endpoint was the effect of CRAC inhibitors on systemic inflammation in acute pancreatitis, as reflected by changes in SIRS scores or plasma C-reactive protein (CRP) levels.

[0437] Administerment of clinical trial materials began within 24 hours of the onset of acute pancreatitis symptoms or within 18 hours of hospital admission. Subjects were randomized 1:1 to receive either one of two doses of a CRAC inhibitor or placebo. Serum levels of the CRAC inhibitor were also monitored at the end of each 2-hour infusion.

[0438] The study lasted for 14 days for each subject, consisting of screening assessment, a subsequent double-blind treatment period of up to 7 days, and a final follow-up visit on day 14. The double-blind treatment period of up to 7 days was part of a minimum 7-day hospitalization observation period.

[0439] Key outcome metrics:

[0440] • Serum concentration of C-reactive protein.

[0441] • SIRS changes over 48 hours

[0442] • Blood amylase and lipase levels.

[0443] Secondary outcome measurement indicators CRAC inhibitors vs. placebo:

[0444] The safety of CRAC inhibitors in this patient population was assessed through routine safety laboratory testing, physical examination and vital sign monitoring, EGG, and adverse event reporting.

[0445] Effects of CRAC inhibitors on other plasma inflammatory markers (interleukin-6, matrix metalloproteinase 9, tumor necrosis factor-α, etc.)

[0446] • The impact of CRAC inhibitors on the clinical course of pancreatitis (based on changes in clinical assessment scales such as the Bedside Index of Severity of Acute Pancreatitis (BISAP), Systemic Inflammatory Response Syndrome (SIRS) and Acute Physiology and Chronic Health Assessment II (APACHE II) scores, as well as contrast-enhanced abdominal computed tomography (CT) scans).

[0447] • Advances in Sequential Organ Failure Assessment (SOFA) scoring

[0448] • Advances in the Multiple Organ Dysfunction Score (MODS)

[0449] Progression of systemic inflammatory response syndrome

[0450] • Progression of inflammation and anti-inflammatory mediators (IL-1RA, IL-10, IL-6, IL-18, TNF-α, ICAM-1, IL-10, etc.).

[0451] • Healthcare staff are being moved to high-dependency or intensive care units and hospital stays are increasing.

[0452] Example 15: Compound I inhibits budding of Junin virus in infected VeroE6 cells

[0453] VeroE6 cells infected with live attenuated Candid-1 JUNV were treated with DMSO, DMSO plus 500 μM TLCS, DMSO plus 500 μM TLCS plus 1 μM CRAC inhibitor compound I, DMSO plus 500 μM TLCS plus 10 μM compound I, DMSO plus 500 μM TLCS plus 25 μM compound I, or DMSO plus 500 μM TLCS plus 50 μM compound I. Infectious virions produced from these cells were quantified using a focus-forming assay. JUNV focus counts revealed a statistically significant dose-dependent reduction in JUNV virus production following compound I treatment.

[0454] These data and Ca 2+ The data together indicate that compound I is effective in inhibiting viral budding of JUNV virus.

[0455] Example 16: Compound I differentially inhibits calcium pool manipulation of Ca 2+ Influx dependence Th1, Th2 and Th17 points change

[0456] Untreated and stimulated mouse T cells cultured under Th1, Th2, and Th17 polarization conditions were treated with DMSO, DMSO plus 500 μM TLCS, or DMSO plus 500 μM TLCS plus 1 μM CRAC inhibitor compound I. The calcium pool was manipulated during each treatment. 2+ SOCE was quantified. Compound I blocked SOCE more strongly in differentiated Th17 cells than in untreated cells, Th1, or Th2 cells. Furthermore, in the presence of compound I, IL-17A production in Th17 cells was more severely affected compared to IFN-γ and IL-4 production in Th1 and Th2 cells, respectively.

[0457] These data and Ca 2+ The expression data, along with those of other transcription factors (i.e., IL-17A, RORα, and RORγt), indicate that compound I is effective in inhibiting Th17 differentiation.

Claims

1. Use of an intracellular calcium signaling inhibitor in the preparation of a medicament for improving symptoms of pancreatitis in humans, wherein the intracellular calcium signaling inhibitor has the following structure: N -(5-(7-chloro-2,3-dihydro-[1,4]dioxacyclohexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl) 3-Fluorophenyl)-2,4,6-trifluorobenzamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl)methyl)aniline, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, or N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, or pharmaceutically acceptable salts thereof.

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

3. The use as claimed in claim 1, wherein the symptoms include at least one of the following: pancreatic inflammation and edema, upper abdominal pain radiating to the back, pain radiating to the upper left quadrant of the back, nausea, vomiting, vomiting that worsens with eating, increased heart rate, tachycardia, increased respiratory rate, increased blood pressure, decreased blood pressure, dehydration, abdominal tenderness, fever, chills, peritonitis, hemodynamic instability, and reflex paralytic ileus.

4. The use as described in claim 1, wherein the symptoms are severe acute pancreatitis symptoms.

5. The use as claimed in claim 1, wherein the symptoms include at least one of pancreatic necrosis and extrapancreatic organ injury.

6. The use as described in claim 1, wherein the symptoms are symptoms of chronic pancreatitis.

7. The use as claimed in claim 1, wherein the symptoms include at least one of the following: persistent abdominal pain, digestive defects, malabsorption of fat, pain during food intake, weight loss, elevated serum amylase activity, elevated serum lipase activity, elevated CRP inflammatory markers, impaired bicarbonate production, elevated fecal elastase levels, elevated serum trypsinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels.

8. The use as claimed in claim 1, wherein the symptoms include at least one of the following: elevated ESR levels, elevated IgG4 levels, elevated rheumatoid factor, presence of ANA antibodies, and presence of anti-smooth muscle antibodies.

9. The use as claimed in claim 1, wherein the symptoms include at least one of the following: steatorrhea, Sudan chemical staining of feces, or 7 g or more of fecal fat excretion within 24 hours after a 100 g fat diet; and a fecal elastase value of less than 200 μg / g in the fecal sample.

10. The use as claimed in claim 1, wherein the symptoms include at least one of the following: abdominal pain, elevated blood amylase levels, elevated blood lipase levels, enlarged pancreas, nausea, vomiting, internal bleeding, paralytic ileus, fever, jaundice, weight loss, and increased heart rate.

11. The use as claimed in claim 1, wherein the symptoms include elevated serum amylase levels.

12. The use as claimed in claim 1, wherein the symptoms include elevated serum lipase levels.

13. The use as claimed in claim 1, wherein the symptoms include necrosis detected by computed tomography (CT) scan.

14. The use as claimed in claim 1, wherein the symptoms include premature activation of digestive enzymes.

15. The use as claimed in claim 14, wherein the premature activation of the digestive enzyme occurs in the pancreas of the person.

16. The use as claimed in claim 14, wherein the enzyme comprises trypsin.

17. Use of an intracellular calcium signaling inhibitor in the preparation of a medicament for the prevention or improvement of pancreatic disease-related symptoms in a person at risk of pancreatic disease, wherein said intracellular calcium signaling inhibitor has the following structure: N -(5-(7-chloro-2,3-dihydro-[1,4]dioxacyclohexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl) 3-Fluorophenyl)-2,4,6-trifluorobenzamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl)methyl)aniline, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, or N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, or pharmaceutically acceptable salts thereof.

18. The use as claimed in claim 17, wherein the pancreatic condition includes symptoms of acute pancreatitis.

19. The use as claimed in claim 17, wherein the pancreatic condition includes symptoms of chronic pancreatitis.

20. The use as claimed in claim 17, wherein the person suffers from pancreatic disease due to a dosing regimen comprising administration of at least one of the following: steroids, HIV drugs, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins, antiglycemic agents, gliptins, or atypical antipsychotics.

21. The use as claimed in claim 20, wherein the steroid is a corticosteroid.

22. The use as described in claim 20, wherein the steroid is prednisolone.

23. The use as described in claim 20, wherein the HIV drug is selected from norinosine and pentamidine.

24. The use as described in claim 20, wherein the statin is a cholesterol-lowering statin.

25. The use as claimed in claim 20, wherein the gliptin is selected from vildagliptin and sitagliptin.

26. The use as described in claim 20, wherein the antihyperglycemic drug is metformin.

27. The use as described in claim 20, wherein the atypical antipsychotic is selected from clozapine, risperidone, and olanzapine.

28. The use as claimed in claim 17, wherein the person is identified as carrying a genetic form of pancreatitis.

29. The use as claimed in claim 28, wherein the human has at least one mutant allele of trypsin 1 encoding trypsinogen, SPINK1 encoding trypsin inhibitor, and cystic fibrosis transmembrane transport regulator.

30. The use as claimed in claim 17, wherein the person suffers from a pancreatic condition caused by at least one of the following: hypercalcemia, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic dysplasia, congenital pancreatic malformation, type 2 diabetes, pancreatic cancer, pancreatic duct stones, vasculitis, Coxsackie virus infection, and porphyria.

31. The use as described in claim 30, wherein the vasculitis is an inflammation of the small blood vessels of the pancreas.

32. The use as claimed in claim 30, wherein the porphyria is selected from acute intermittent porphyria and erythropoietic protoporphyria.

33. The use as described in claim 17, wherein the person's health condition has been affected by at least one of the following: gallstones, alcohol poisoning, trauma, mumps, autoimmune disease, scorpion sting, hyperlipidemia, hypothermia, hyperparathyroidism, endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid.

34. The use as described in claim 33, wherein the alcohol poisoning is alcohol poisoning.

35. The use as claimed in claim 17, wherein the person's health condition has been affected by at least one of the following: Coxsackie virus, cytomegalovirus, hepatitis B virus, herpes simplex virus, mumps, varicella-zoster virus, Legionella bacteria, Leptospira bacteria, Mycoplasma bacteria, Salmonella bacteria, Aspergillus fungi, Ascaris parasites, Cryptosporidium cells, and Toxoplasma cells.

36. Use of an intracellular calcium signaling inhibitor in the preparation of a medicament for a dosing regimen, wherein the dosing regimen comprises administering to an individual a medicament associated with a negative effect on pancreatic activity, and administering an intracellular calcium signaling inhibitor or a pharmaceutically acceptable salt thereof, said intracellular calcium signaling inhibitor having the following structure: N -(5-(7-chloro-2,3-dihydro-[1,4]dioxacyclohexano[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl) 3-Fluorophenyl)-2,4,6-trifluorobenzamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazolyl)methyl)aniline, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazolyl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazolyl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, or N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, or pharmaceutically acceptable salts thereof.

37. The use as described in claim 36, wherein the drug associated with the negative effect on pancreatic activity is selected from corticosteroids, HIV drugs, diuretics, valproic acid, L-asparaginase, azathioprine, estrogens, statins, antiglycemic agents, gliptins, and atypical antipsychotics.

38. The use as described in claim 37, wherein the corticosteroid is prednisolone.

39. The use as described in claim 37, wherein the HIV drug is selected from norinosine and pentamidine.

40. The use as described in claim 37, wherein the statin is a cholesterol-lowering statin.

41. The use as described in claim 37, wherein the antihyperglycemic drug is metformin.

42. The use as claimed in claim 37, wherein the gliptin is selected from vildagliptin and sitagliptin.

43. The use as described in claim 37, wherein the atypical antipsychotic is selected from clozapine, risperidone, and olanzapine.

44. A compound, wherein the compound has the following structure: N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisocyanamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 3-fluoro-4-(1-methyl) 3,5-difluoro-N-(3-fluoro-4-(3-methylisothiazol-4-yl)methyl)aniline, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazole-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazol-2-yl)-1H-pyrazole-4-yl)phenyl)isonicotinamide, or N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, or pharmaceutically acceptable salts thereof.

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