Pyrazine-containing compound
Inventors
Velicelebi, Gonul • Stauderman, Kenneth • Dunn, Michael • Roos, Jack
Assignees
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Publication Number
US-11752148-B2
Publication Date
2023-09-12
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 invention relates to calcium-signaling-modulating small-molecule inhibitors for therapeutic treatment of pancreatitis. The description focuses on inhibition of intracellular calcium signaling, including pancreatic CRAC/SOC-mediated Ca2+ influx through targeting calcium entry pathways that involve STIM1 and Orai.
The disclosed approach treats acute and chronic pancreatitis by administering a therapeutically effective amount of the inhibitors to ameliorate pancreatitis outcomes described in terms of edema, inflammation, necrosis, abdominal pain, elevated blood amylase and blood lipase, enlarged pancreas, and necrosis-related outcomes including organ failure, pancreas necrosis, and death. The document also describes reducing severity, likelihood, and/or duration, stopping progression, and preventing severe outcomes.
The calcium-signaling approach is also extended to other disease settings described in the document, including viral hemorrhagic-fever diseases via STIM1/Orai-mediated calcium entry that supports viral budding/replication. Additionally, Th17-induced chronic inflammatory and autoimmune diseases are addressed by inhibiting Ca2+ channel functions and by inhibiting Th17 differentiation, including reduced IL-17A and Th17-associated transcription factors.
Claims Coverage
The provided material includes independent claims directed to a specific named compound and to treating pancreatitis by administering a therapeutically effective amount of specified small-molecule compounds or salts. Additional dependent claims characterize chronic pancreatitis, pancreatitis associated with an inflammatory response, Th17-induced chronic inflammatory disease, oral administration, and inhibiting Th17 differentiation.
Specific named pyrazine-containing compound with salt coverage
A compound having the chemical name N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine or a pharmaceutically acceptable salt thereof.
Therapeutically effective pancreatitis treatment using specified small-molecule inhibitors
A method for treating pancreatitis in a subject by administering to the subject a therapeutically effective amount of a compound having the chemical name N-(5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, or N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, or a pharmaceutically acceptable salt thereof.
Oral administration
The method where the administering is oral, and the pharmaceutical composition is formulated as an oral composition.
Chronic pancreatitis and inflammatory-response-associated pancreatitis
The pancreatitis treatment is narrowed to chronic pancreatitis and to pancreatitis in a subject associated with an inflammatory response.
Th17 differentiation inhibition
The method further includes inhibiting Th17 differentiation in a context involving Th17-induced chronic inflammatory disease.
Overall, the claim coverage centers on a specifically named inhibitor and a pancreatitis treatment method that administers a therapeutically effective amount of specified inhibitor alternatives, with dependent limitations narrowing to oral administration, chronic pancreatitis, inflammatory-response association, and inhibition of Th17 differentiation.
Stated Advantages
Treating pancreatitis in a subject.
Reducing severity, likelihood, and/or duration, including stopping progression.
Preventing severe outcomes including organ failure, pancreas necrosis, and death.
Inhibiting Th17 differentiation and reducing IL-17A and Th17-associated transcription factors.
Ameliorating acute and chronic pancreatitis by inhibiting pancreatic CRAC/SOC-mediated Ca2+ influx.
Reducing risk/severity of pancreatitis.
Supporting treatment beyond pancreatitis by targeting STIM1/Orai-mediated calcium entry described as supporting viral budding/replication in viral hemorrhagic-fever diseases.
Addressing Th17-induced chronic inflammatory and autoimmune diseases by inhibiting Ca2+ channel functions and inhibiting Th17 differentiation.
Documented Applications
Prophylactic and therapeutic treatment/amelioration concepts for pancreatitis, including halting progression and preventing severe outcomes such as organ failure, pancreas necrosis, and death.
A Phase II clinical trial framework for intravenous CRAC inhibitors in acute pancreatitis using endpoints including SIRS/CRP and pancreatic enzymes.
Prophylaxis in other indications including viral diseases and hemorrhagic fever viruses.
Inhibition of viral budding (Junin virus in VeroE6) is described.
Prophylaxis in Th17-induced diseases.
Treatment/amelioration of acute and chronic pancreatitis in a subject by administering therapeutically effective amounts of the disclosed inhibitors.
Treatment of viral hemorrhagic-fever diseases described in the document via inhibition of STIM1/Orai-mediated calcium entry supporting viral budding/replication.
Treatment of Th17-induced chronic inflammatory and autoimmune diseases by inhibiting Ca2+ channel functions and inhibiting Th17 differentiation.
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