Substituted-3H-imidazo[4,5-c]pyridine and 1H-pyrrolo[2,3-c]pyridine series of novel Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) and stimulator for interferon genes (STING) modulators as cancer immunotherapeutics
Inventors
Vankayalapati, Hariprasad • Sharma, Sunil • Kaadige, Mohan Rao • Weston, Alexis • Thode, Trason
Assignees
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Publication Number
US-11142524-B2
Publication Date
2021-10-12
Expiration Date
Abstract
Substituted -3H-imidazo[4,5-c]pyridine and 1H-pyrrolo[2,3-c]pyridine series of novel Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) and related compounds, which are useful as inhibitors of ENPP1; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds and compositions to treat disorders associated with dysfunction of the ENPP1.
Core Innovation
The disclosure relates to small-molecule ENPP1 inhibitors and ENPP1-modulating STING pathway activators for use in cancer immunotherapy. The invention provides compounds of Formula I in substituted imidazo[4,5-c]pyridine and 1H-pyrrolo[2,3-c]pyridine series, with defined substituent variables and coverage for stereoisomers, isotopic variants, tautomers, polymorphic forms, hydrates, solvates, and pharmaceutically acceptable salts.
The described compounds are linked to ENPP1 dysfunction and the cGAMP/cGAS pathway, with downstream IFN-β, NF-κB, and IRF3 effects. The disclosure states that inhibiting ENPP1 activity is associated with treating uncontrolled cellular proliferation, including cancer and tumor, and with treating infectious diseases, including bacterial and viral infections, and it also states use as medicaments and in pharmaceutical compositions for administration to a mammal.
The material further includes substituted acetamide/thioether analogs and imidazo[4,5-c]pyridine thioether derivatives, together with named intermediates and final products. Additional sections describe synthesis, purification, and analytical characterization of multiple ENPP1 inhibitor compounds, including structure-based computational docking and binding free energies, in vitro ENPP1 activity assays, thermal shift assay, synergy studies with olaparib, and in vivo anti-tumor efficacy in mouse models.
Claims Coverage
The provided claim content centers on one independent compound claim and a dependent pharmaceutical composition claim, giving two inventive features overall. The recurring scope is a compound selected from a defined group, including an isomer or a pharmaceutically acceptable salt, together with formulation as a pharmaceutical composition containing a therapeutically effective amount and a pharmaceutically acceptable carrier.
Compound selected from defined group with isomers and pharmaceutically acceptable salts
A compound selected from the group consisting of the defined compounds, including an isomer of the compound and a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with therapeutically effective amount and pharmaceutically acceptable carrier
A pharmaceutical composition comprising a therapeutically effective amount of a compound of the defined group together with a pharmaceutically acceptable carrier.
The claims are directed to defined ENPP1 inhibitor compounds, expressly including isomers and pharmaceutically acceptable salts, and to pharmaceutical compositions comprising a therapeutically effective amount of such compounds with a pharmaceutically acceptable carrier.
Stated Advantages
Treating uncontrolled cellular proliferation, including cancer and tumor.
Treating infectious diseases, including bacterial and viral infections.
Decreasing or inhibiting ENPP1 activity and eliciting an immunotherapeutic response in mammals.
Documented Applications
Therapeutic methods for disorders associated with ENPP1 dysfunction, including ENPP1 activity inhibition and eliciting an immunotherapeutic response in mammals.
Treatment of uncontrolled cellular proliferation such as cancer and tumor.
Treatment of infectious diseases including bacterial and viral infections.
Use as a medicament for administration to a mammal in pharmaceutical compositions.
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