Pyrazine-containing compound
Inventors
Velicelebi, Gonul • Stauderman, Kenneth • Dunn, Michael • Roos, Jack
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11439639-B2
Publication Date
2022-09-13
Expiration Date
Abstract
Compositions and methods related to the amelioration of pancreatitis through the pharmaceutical manipulation of calcium signaling are disclosed. Such compositions and methods may be used to ameliorate symptoms of acute or chronic pancreatitis or to reduce the chance or severity of pancreatitis in an individual at risk of the condition. In other embodiments, disclosed herein are compositions and methods related to the amelioration of viral diseases through the pharmaceutical manipulation of calcium signaling. In further embodiments, disclosed herein are compositions and methods related to the amelioration of Th17-induced diseases through the pharmaceutical manipulation of calcium signaling.
Core Innovation
The disclosed subject matter addresses intracellular Ca2+ signaling in pancreatic acinar cells and identifies intracellular calcium signaling inhibitors as therapeutic and prophylactic agents to ameliorate acute and chronic pancreatitis. The invention provides intracellular calcium signaling inhibitors directed to SOC/CRAC/STIM1/Orai1/Orai2 calcium entry (SOCE/ICRAC) to treat disease states associated with excessive intracellular Ca2+ signaling.
The pathologic sequence includes premature trypsin activation, pancreatic autodigestion, necrosis, inflammation, edema, and extra-pancreatic organ injury, with drivers including bile acids, fatty acid ethyl esters, CCK hyperstimulation, and CRAC channel activation. The described approach aims to mitigate these outcomes by inhibiting CRAC/SOC calcium entry, including in pancreatitis and related inflammatory disease contexts.
The disclosure further defines Compound A and related compounds as specific pyrazine-containing benzamides and analogs, including the named example N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, in free form, salts, solvates, prodrugs, and optionally nanoparticle formulations. Supporting content also includes compound examples such as Compound I, GSK-7975A, Compound II, and Compound III, with tissue concentrations tied to in vitro IC50 values and broader outcomes including cytokine inhibition and reductions in serum amylase/lipase.
Claims Coverage
Two independent claims are present. Across the claims, the coverage centers on administering a therapeutically effective amount of the specified carboxamide compound or a pharmaceutically acceptable salt to treat kidney-linked disease states associated with inflammation or Th17-induced autoimmunity, with dependent claims further adding inflammatory mediators and plasma concentration targets.
Treating renal failure secondary to pancreatitis inflammatory response
A method for treating renal failure in a subject by administering a therapeutically effective amount of N-[5-(6-chloro-2,2-difluorobenzo[d]1,3-dioxolen-5-yl)pyrazin-2-yl](2-fluoro-6-methylphenyl)carboxamide or a pharmaceutically acceptable salt, wherein the renal failure is a secondary manifestation of pancreatitis resulting from an inflammatory response.
Treating Th17-induced autoimmune disease in a kidney
A method for treating an autoimmune disease in a kidney in a subject by administering a therapeutically effective amount of N-[5-(6-chloro-2,2-difluorobenzo[d]1,3-dioxolen-5-yl)pyrazin-2-yl](2-fluoro-6-methylphenyl)carboxamide or a pharmaceutically acceptable salt thereof, wherein the autoimmune disease is Th17 induced.
The claim set covers administration of the specified carboxamide compound to treat renal failure as a secondary manifestation of pancreatitis driven by an inflammatory response and Th17-induced autoimmune disease in a kidney, with dependent claims further specifying inflammatory mediators, chronic inflammatory disease association, autoimmune disorder classification, and plasma concentration targets.
Stated Advantages
Amelioration of pancreatitis by inhibiting SOC/CRAC/STIM1/Orai1/Orai2 calcium entry.
Mitigation of excessive ER Ca2+-release-linked hyperactivation of CRAC channels and downstream processes including premature trypsin activation, pancreatic autodigestion, and pancreatic necrosis.
Reduction of extra-pancreatic organ injury, inflammation, and edema associated with pancreatitis.
Amelioration of viral and Th17-induced diseases.
Documented Applications
Ameliorating pancreatitis, including acute or chronic pancreatitis.
Preventing pancreatitis in at-risk individuals.
Ameliorating renal failure as a secondary manifestation of pancreatitis resulting from an inflammatory response.
Treating Th17-induced autoimmune disease in a kidney.
Ameliorating viral diseases including hemorrhagic fever virus examples: Ebola, Marburg, Lassa, Junin, and Zika.
Ameliorating Th17-induced diseases and Th17-related autoimmune disease contexts.
Interested in licensing this patent?