Azolopyrimidine for the treatment of cancer-related disorders
Inventors
BEATTY, Joel • DEBIEN, Laurent • JEFFREY, Jenna • Leleti, Manmohan Reddy • MANDAL, Debashis • MILES, Dillon • Powers, Jay • ROSEN, Brandon • SHARIF, Ehesan • THOMAS-TRAN, Rhiannon
Assignees
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Publication Number
US-12195447-B2
Publication Date
2025-01-14
Expiration Date
Abstract
Compound that is an inhibitor of at least one of the A2A and A2B adenosine receptors, and compositions containing the compound and methods for synthesizing the compound, are described herein. The use of such compound and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related disorders that are mediated, at least in part, by the adenosine A2A receptor and/or the adenosine A2B receptor.
Core Innovation
The disclosure provides azolopyrimidine small-molecule antagonists/inhibitors that target adenosine A2A and/or adenosine A2B receptors. The disclosed compounds are presented as Formula (I) compounds, including variants Ia–Ie and an example Compound I, together with pharmaceutically acceptable salts and related forms.
The document also describes strategies for improving the pharmacokinetic and biological properties of adenosine A2A/A2B receptor inhibitors. Reported approaches include PEGylation, Fc-albumin fusion or albumin fusion, and deuteration, which are presented as ways to improve water solubility, bioavailability, serum half-life, and therapeutic half-life, while inhibiting adenosine A2AR/A2BR mediated immunosuppression and supporting vaccine efficacy.
In addition, the disclosure includes pharmaceutical compositions and formulation approaches for the described A2A/A2BR inhibitors, including routes and dosage forms and the use of pharmaceutically acceptable excipients. It also provides general assay concepts and extensive chemistry examples for specific A2A/A2BR inhibitor compounds, including a cAMP functional assay concept and synthetic chemistry schemes and examples.
Claims Coverage
The consolidated claim coverage centers on selected compounds or pharmaceutically acceptable salts thereof, with dependent coverage adding pharmaceutical compositions comprising the selected compound or salt together with a pharmaceutically acceptable excipient. Across the items, the independent claim scope repeatedly covers compound selection as the primary inventive feature.
Selected compound or pharmaceutically acceptable salt
A compound selected from the group consisting of the recited compound(s) or the disclosed compound set, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the selected compound or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient.
Overall, the claims are directed to selection of the described compound(s) or salt form(s), and to pharmaceutical compositions that include the selected compound or salt plus a pharmaceutically acceptable excipient.
Stated Advantages
Inhibition potency against adenosine A2A and/or A2B receptors is described as <10 nM.
Improved water solubility.
Improved bioavailability.
Improved serum half-life.
Improved therapeutic half-life.
Counteracting adenosine A2AR/A2BR mediated immunosuppression to maintain or enhance immune response, including vaccine efficacy.
Broad therapeutic positioning is described for cancer, immune/inflammatory disorders, and infectious disorders, including viral infections such as HIV and CMV.
Combination therapy with immune checkpoint inhibitors, chemotherapeutics, signal transduction inhibitors, radiotherapy, immunomodulators, and vaccines is described.
Documented Applications
Cancer.
Immune/inflammatory disorders, including RA and psoriasis.
Infective disorders, including viral infections such as HIV and CMV.
Modulating immune responses by inhibiting adenosine A2AR/A2BR mediated immunosuppression, including effects on regulatory T-cells (Tregs) and CD8+ T-cells and supporting vaccine efficacy.
Combination therapy with immune checkpoint inhibitors targeting PD-1, PD-L1, CTLA-4, TIGIT, LAG-3, TIM-3, and 2B4 (CD244).
Use in CNS/neurological and cardiovascular/metabolic indications, as described in the document.
Combination therapy with other therapeutics, as described in the document.
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