Inhibitors of sodium glucose cotransporter 1
Inventors
Carson, Kenneth Gordon • Goodwin, Nicole Cathleen • Harrison, Bryce Alden • Rawlins, David Brent • Strobel, Eric • Zambrowicz, Brian
Assignees
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Publication Number
US-9688710-B2
Publication Date
2017-06-27
Expiration Date
Abstract
Inhibitors of sodium glucose cotransporter 1 (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed. Particular compounds are of the formula: the various substituents of which are defined herein.
Core Innovation
The invention concerns the specific compound N-(1-((2-(dimethylamino)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide, and pharmaceutically acceptable salts thereof. The disclosed subject matter also includes related analogs and derivatives, including amide and later amide/urea/guanidine derivatives, together with described prodrug or salt forms such as formate and bisformate salts.
The patent discloses selective SGLT1 inhibitor compounds defined by general chemical formulas and specific embodiments, characterized as local gut acting compounds with selective SGLT1 inhibition. Potency is presented using SGLT1 IC50 values, including <50/25/10 nM, and the disclosure links the compounds to biological effects that include plasma tGLP-1 and modulation of glucose-related outcomes.
The document includes pharmaceutical compositions and solid oral dosage forms, including tablets, capsules, and liquids, with excipient admixture and optional polymer/bead binding for enteric delivery. The overall emphasis is on delivering SGLT1 inhibitors with low systemic exposure, using Cmax thresholds as a stated basis for local gut action, and on therapeutic use in diabetes and other cardiometabolic and bowel disease contexts.
Claims Coverage
The consolidated claim set includes two independent claim categories. The inventive features center on a specific named N-(...)-butanamide SGLT1 inhibitor compound (or pharmaceutically acceptable salt) and a method of treating or managing diabetes by administering a therapeutically effective amount of that compound.
Specific N-(...)-butanamide SGLT1 inhibitor compound
A compound, which is N-(1-((2-(dimethylamino)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide, or a pharmaceutically acceptable salt thereof.
Treating or managing diabetes by administering a therapeutically effective amount
A method of treating or managing diabetes comprises administering to a patient in need thereof a therapeutically effective amount of N-(1-((2-(dimethylamino)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide, or a pharmaceutically acceptable salt thereof.
Overall, claim coverage centers on the specific named N-(...)-butanamide compound and on diabetes treatment or management by administering a therapeutically effective amount of that compound to a patient in need. Dependent claim coverage further specifies pharmaceutical composition with excipient or diluent and solid oral dosage forms such as tablets or capsules, and narrows the diabetes indication to type 1 diabetes or type 2 diabetes.
Stated Advantages
Selective SGLT1 inhibition with potency described by SGLT1 IC50 values, including <50/25/10 nM.
Local gut acting compounds with low systemic exposure supported by Cmax thresholds.
Ability to modulate GLP-1-related and glucose-related outcomes, as reflected by stated figure readouts including GLP-1, HbA1c, cecal glucose, and plasma tGLP-1.
Documented Applications
Treating or managing diabetes, including type 1 diabetes and type 2 diabetes, using the specified N-(...)-butanamide compound or a pharmaceutically acceptable salt.
Treating or managing cardiovascular diseases/disorders, metabolic diseases/disorders, and bowel diseases/disorders, including constipation-predominant IBS (IBS-C) and chronic constipation.
Treating certain cancers in which SGLT gene expression is enhanced.
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