Treatments of gastrointestinal disorders
Inventors
Currie, Mark G. • Fretzen, Angelika • Kessler, Marco • Zimmer, Daniel
Assignees
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Publication Number
US-8946158-B2
Publication Date
2015-02-03
Expiration Date
Abstract
The present invention provides peptides that are useful for the treatment of gastrointestinal disorders. The present invention also provides compositions and methods of treating gastrointestinal disorders and pharmaceutical compositions for accomplishing the same. In some embodiments, these pharmaceutical compositions include oral dosage forms.
Core Innovation
The document describes a method for treating a gastrointestinal disorder by administering a peptide or a pharmaceutically acceptable salt thereof. The peptide comprises the amino acid sequence identified as SEQ ID NO:1 with an allowed pattern of amino-acid substitutions at multiple positions, together with conditional amino-group modifications and optional modifications depending on whether certain residues are present or absent.
The core concept is that GC-C agonist activity is associated with cGMP-based pharmacology and is supported at the level of peptide design. The document ties phosphoamino acid inclusion to stronger GC-C agonist action in the upper GI and describes that the peptide is designed to be dephosphorylated by intestinal alkaline phosphatases during transit.
The patent further characterizes the peptides through extensive variant coverage, including specific sequence identifiers, salts, and optional disulfide or crosslink variants, and discusses oral administration compositions. Mechanistic and in vivo support is described using phosphatase sensitivity and dephosphorylation profiles, GC-C activity linked to cGMP accumulation and binding affinity at different pH, and gastrointestinal effects such as accelerated upper GI transit and duodenal fluid and bicarbonate secretion.
Claims Coverage
Independent inventive claim covers a method for treating gastrointestinal disorders by administering a GC-C agonist peptide, or a pharmaceutically acceptable salt, defined by SEQ ID NO:1 with specific allowed amino-acid options at multiple positions and conditional amino-group modifications. The claim set additionally narrows to specific gastrointestinal disorders and peptide examples, and further refines formulation components in dependent claims.
Treating a gastrointestinal disorder with a SEQ ID NO:1 phosphoamino-acid peptide
A method for treating a gastrointestinal disorder comprising administering a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence SEQ ID NO:1 with Xaa1, Xaa2, Xaa3, Xaa4, Xaa6, Xaa7, Xaa8, Xaa14, Xaa16, and Xaa17 defined by specified options, including phosphoamino acids at Xaa6, and wherein conditional amino-group modifications on certain residues are specified when Xaa1 and/or Xaa2 are present or absent.
Across the independent claim, the inventive coverage is directed to administering a defined SEQ ID NO:1 peptide salt for treating a gastrointestinal disorder, where the peptide’s phosphoamino-acid-containing position and allowable residue options, together with conditional amino-group modifications, are central to the claimed scope.
Stated Advantages
Aims for stronger GC-C agonist activity in the upper GI.
Is designed to be dephosphorylated by intestinal alkaline phosphatases during transit to reduce lower-GI effects.
Provides cGMP-based pharmacological outcomes including pain relief and fluid/bicarbonate secretion.
Aims to accelerate upper GI transit.
Aims to minimize diarrhea-like adverse effects.
Documented Applications
Treating upper gastrointestinal disorders, including functional dyspepsia, gastroparesis, post-operative gastric ileus, functional esophageal disorder, functional gastroduodenal disorder, gastroesophageal reflux disease, celiac disease, mucositis, duodenal ulcer, and stomach ulcer.
Mechanistic and in vivo evaluation in mice GI transit, rat ligated intestinal loops with duodenal fluid and bicarbonate secretion, jejunal metabolism and stability in loop fluid, and effects on liquid gastric emptying in STZ-induced diabetic rats.
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