JPWO2021236820A5 - - Google Patents

Claims (22)

1. An intracellular calcium signaling inhibitor for use in a method for treating acute kidney injury (AKI) in a subject, said method comprising administering a therapeutically effective amount of said intracellular calcium signaling inhibitor to said subject. 1. An intracellular calcium signaling inhibitor for use in a method for preventing acute kidney injury (AKI) in a subject at risk of developing AKI, said method comprising administering a prophylactically effective amount of said intracellular calcium signaling inhibitor to said subject. An intracellular calcium signaling inhibitor for use in a method for preventing or delaying the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) in a subject, said method comprising administering a prophylactically effective amount of said intracellular calcium signaling inhibitor to said subject. The intracellular calcium signaling inhibitor according to claim 1 or 2, wherein the intracellular calcium signaling inhibitor is a store-operated calcium (SOC) channel inhibitor. The intracellular calcium signaling inhibitor according to claim 1 or 2, wherein the intracellular calcium signaling inhibitor is a Ca2+ release-activated (CRAC) channel inhibitor. The intracellular calcium signaling inhibitor according to claim 1 or 2, wherein the intracellular calcium signaling inhibitor inhibits a channel containing the stromal interaction molecule 1 (STIM1) protein. The intracellular calcium signaling inhibitor according to claim 1 or 2, wherein the intracellular calcium signaling inhibitor inhibits a channel containing the Orai1 protein. The intracellular calcium signaling inhibitor according to claim 1 or 2, wherein the intracellular calcium signaling inhibitor inhibits a channel containing the Orai2 protein. The intracellular calcium signaling inhibitor is selected from the group consisting of N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, and N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide. N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazole-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluoro 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-(trifluorophenyl)-2,6-difluorobenzamide, fluoromethyl)-1H-pyrazol-5-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazol-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluoro 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazol-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-difluorobenz ... trifluorobenzyl)pyridin-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)-2, The intracellular calcium signaling inhibitor according to claim 1 or 2, which is a compound having a structure of 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]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharma- ceutical acceptable salt, a pharma-ceutical acceptable solvate, or a pharma-ceutical acceptable prodrug thereof. The intracellular calcium signaling inhibitor according to claim 8, wherein the intracellular calcium signaling inhibitor is a compound having the chemical name N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin)-2-yl)-2-fluoro-6-methylbenzamide, or a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate, or a pharma- ceutically acceptable prodrug thereof. The intracellular calcium signaling inhibitor according to claim 8, wherein the intracellular calcium signaling inhibitor is a compound having the chemical name 2,6-difluoro-N-(1-(4-hydroxy-2-(trifluoromethyl)benzyl)-1H-pyrazol-3-yl) benzamide, or a pharma- ceutically acceptable salt, a pharma-ceutically acceptable solvate, or a pharma-ceutically acceptable prodrug thereof. The method according to any one of claims 1 to 11, further comprising the step of inhibiting differentiation of CD4+ T cells into T helper 17 (TH17) cells . The method of claim 12, wherein the differentiation of CD4+ T cells into TH17 cells occurs in the kidney. The method of any one of claims 1 to 13, wherein the method further comprises the step of decreasing the amount of interleukin 17 (IL-17), a pro-inflammatory cytokine. 15. The intracellular calcium signaling inhibitor of any of claims 1 to 14, wherein the method further comprises administering a second compound selected from the group consisting of recombinant human IGF-I (rhIGF-I), atrial natriuretic peptide (ANP), dopamine, a caspase inhibitor, minocycline, guanosine and pifithrin-α (p53 inhibitor), poly ADP-ribose polymerase inhibitors, deferoxamine, ethyl pyruvate, activated protein C, insulin , recombinant erythropoietin, hepatocyte growth factor, carbon monoxide releasing compounds, bilirubin, endothelin antagonists, sphingosine 1 phosphate analogs, adenosine analogs, inducible nitric oxide synthase inhibitors, fibrates, neutrophil gelatinase-associated lipocalin, IL-6 antagonists, C5a antagonists, IL-10, dexmedetomidine, chloroquine (CQ), hydroxychloroquine (HCQ), and α-melanocyte stimulating hormone. A composition comprising an intracellular calcium signaling inhibitor and at least a compound for treating acute kidney injury (AKI). 17. The composition of claim 16, wherein the compound is selected from the list consisting of recombinant human IGF-I (rhIGF-I), atrial natriuretic peptide (ANP), dopamine, caspase inhibitors, minocycline, guanosine and pifithrin-α (p53 inhibitors), poly ADP-ribose polymerase inhibitors, deferoxamine, ethyl pyruvate, activated protein C, insulin, recombinant erythropoietin, hepatocyte growth factor, carbon monoxide releasing compounds, bilirubin, endothelin antagonists, sphingosine 1 phosphate analogs, adenosine analogs, inducible nitric oxide synthase inhibitors, fibrates, neutrophil gelatinase-associated lipocalin, IL-6 antagonists, C5a antagonists, IL-10, dexmedetomidine, chloroquine (CQ), hydroxychloroquine (HCQ), and α-melanocyte stimulating hormone. A dosing regimen comprising administering to a subject a compound for treating acute kidney injury (AKI) and administering an intracellular calcium signaling inhibitor. A composition for the prevention of acute kidney injury (AKI) in a subject at risk of developing AKI , comprising the administration of a therapeutically effective amount of an inhibitor of intracellular calcium signaling. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 9 and a pharma- ceutical acceptable excipient. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 10 and a pharma- ceutical acceptable excipient. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 11 and a pharma- ceutical acceptable excipient.