Highly active compounds against COVID-19

Inventors

Sommadossi, Jean-Pierre • Moussa, Adel

Assignees

Atea Pharmaceuticals Inc

Abstract

The present invention is the use of a small group of purine nucleotide phosphoramidate disclosed herein or a pharmaceutically acceptable salt thereof in an effective amount for the treatment or prevention of the novel 2019 coronavirus disease (COVID-19) in a host, for example a human, in need thereof.

Core Innovation

The invention relates to antiviral purine nucleoside analogs and a small group of purine nucleotide phosphoramidate compounds represented by Formula I-V, including Compound 1, Compound 1A, Compound 1B, Compound 2, Compound 2A, Compound 2B, Compound 3, Compound 3A, Compound 3B, Compound 4, Compound 4A, and Compound 4B, together with pharmaceutically acceptable salts and hemi-sulfate salt forms. Chemical structures, preparation, stabilized phosphate prodrug embodiments, and additional phosphoramidate compound structures with variable substituents for groups R^P1 and R^P2 are described. The disclosure also includes isotopic substitution, including enriched deuterium and ^13C, and chirality at the phosphorus stereocenter as R_p/S_p mixtures.

The subject matter addresses treatment and prevention of coronavirus infection, including treatment of a coronavirus in a human in need thereof and treatment or prevention of COVID-19 caused by SARS-CoV-2. It includes administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable carrier, and further states prophylaxis and clinical endpoints such as reduced time to clinical recovery and improved respiratory support. The document also discusses progressive respiratory insufficiency (PRI), pharmaceutical compositions, and dosage forms.

The disclosure reports biological evaluation of Compound 1A and related compounds in Huh7, BHK-21, and MES-1 cells, including in vitro coronavirus activity, cytotoxicity, efficacy endpoints, virus-yield reduction assays, and protection-related endpoints. It further reports selective antiviral activity and intracellular metabolite formation, including an active triphosphate metabolite in airway epithelial cells and a triphosphate half-life greater than about 1.5 days in primary bronchial/nasal epithelial cells. In non-human primates, active triphosphate concentrates in lung over liver after twice-daily oral dosing of Compound 2A.

The document further states a metabolic pathway in which a phosphoramidate converts through de-esterification to downstream monophosphate, diphosphate, and triphosphate, together with measurable surrogate metabolite(s). It also states that the mechanism is not solely explained by RdRp inhibition.

Claims Coverage

The independent claim coverage centers on a method of treating a coronavirus in a human by administering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. Across the claims provided, there are six inventive features, including administration of Compound 1, use of a pharmaceutically acceptable salt, optional carrier use, and dependent refinements to specific coronavirus strains, dosage form characteristics, and one explicit oral twice-daily regimen for Compound 2A hemisulfate salt.

Overall, the claim coverage centers on administering an effective amount of Compound 1, or a pharmaceutically acceptable salt, in a pharmaceutically acceptable carrier to treat a coronavirus in a human, with dependent features specifying particular coronavirus strains, carrier suitability for intravenous delivery, solid dosage form formats, and an explicit oral twice-daily regimen for Compound 2A hemisulfate salt.

Stated Advantages

Documented Applications