Phosphorylated A2a Receptor Agonists

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This patent describes a new class of phosphorylated A2A receptor agonists that, after dephosphorylation in the body, activate the A2A adenosine receptor. These compounds, distinguished from natural adenine nucleotides (AMP, ADP, ATP), act as prodrugs that are converted at sites of inflammation or tissue injury by the enzyme CD73 into active A2A agonists, which have potent anti-inflammatory properties. The invention includes methods and formulations for using these compounds to treat diseases associated with acute or chronic inflammatory, hypotensive, psychotic, or asthmatic events, and is especially relevant to conditions involving immune response and tissue transplantation.

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• Treatment of acute and chronic inflammatory diseases (e.g., arthritis, Crohn’s disease, arteriosclerosis)
• Prevention or reduction of inflammation following organ, tissue, or cell transplantation (such as heart, kidney, cornea, bone marrow, or pancreatic islets)
• Adjunctive therapy in infectious diseases (bacterial, viral, or fungal) to control associated inflammation
• Therapy for vascular injuries, such as restenosis after angioplasty or traumatic spinal cord injury
• Management of immune-mediated rejections and graft-versus-host disease
• Treatment of inflammation associated with bio-terrorism agents (e.g., anthrax, plague) when used with antibiotics or other anti-infective agents

BenefitsContent extracted from patent full text and abstract with AI.

• Site-specific activation: Prodrugs are activated locally at inflamed or injured sites where CD73 is upregulated, leading to targeted therapy and potentially reduced systemic side effects.
• Enhanced anti-inflammatory action: Directly addresses localized excessive immune or inflammatory responses, helping to resolve inflammation more effectively.
• Versatility: Can be used alone or in combination with existing anti-infective therapies, broadening the therapeutic range.
• Reduced systemic exposure: Lower doses may be needed due to localized activation, minimizing risks of unwanted side effects seen with systemic A2A agonists.
• Potential for better graft and transplant outcomes: By controlling immune response and inflammation, these compounds can help prevent rejection or injury of transplanted tissues.
• Potential utility in a wide variety of diseases and emergencies, from chronic inflammation to acute trauma, sepsis, and infectious disease outbreaks.
• Adjunct to non-invasive diagnostics: Targeting CD73 may also facilitate imaging or identification of high-risk inflammatory vascular lesions.

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Patent Abstract

A phosphorylated A2A receptor agonist providing agonist properties on the A2A receptor after dephosphorylation the phosphorylated A2A receptor agonist comprises a ribosyl moiety and a purine moiety and being phosphorylated at the 5'-position of the ribose moiety except adenosine monophosphate (AMP), adenosine diphosphate (ADP) or adenosine triphosphate (ATP), a medicament containing the compound of the invention including ADP and the use of the compound of the invention including ATP and ADP for several medical indications e. g. inflammatory events. In particular, compounds of formula (I) are also disclosed.