α4β7 thioether peptide dimer antagonists
Inventors
Bhandari, Ashok • Patel, Dinesh V. • Zemede, Genet • Frederick, Brian Troy • Mattheakis, Larry C. • Liu, David
Assignees
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Publication Number
US-11840581-B2
Publication Date
2023-12-12
Expiration Date
Abstract
The invention relates to thioether monomer and dimer peptide molecules which inhibit binding of α4β7 to the mucosal addressing cell adhesion molecule (MAdCAM) in vivo.
Core Innovation
The invention provides thioether cyclized peptide monomers and peptide dimers that antagonize integrin α4β27 by inhibiting α4β27 binding to MAdCAM in vivo. The compounds include a thioether bond between 2-methylbenzoyl and Pen, with monomer and dimer designs specified by permissible substituents and selectable amino-acid positions across a defined sequence framework.
The invention provides a peptide dimer compound, or a pharmaceutically acceptable salt thereof, for treating or preventing inflammatory bowel disease in a subject in need thereof. Each peptide comprises the sequence 2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homo-Glu)-(D-Lys), and the two peptides are linked by a linker moiety.
The linker moiety includes DIG (diglycolic acid), PEG-based spacers including PEG4, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, and PEG5K, and peptide/linker variations with biotin such as PEG4-biotin and IDA-biotin. The patent further states that linker moieties can also include amino-diacid and functional spacers such as IDA, ADA, Boc-IDA, Ac-IDA, AADA, and GTA/dicarboxylic acids.
The document also describes improved binding potency/selectivity to α4β27 integrin versus α4β21, improved gastrointestinal stability in simulated intestinal fluid and simulated gastric fluid under reduced conditions, redox stability, and an imaging-related concept using orally stable, chelated/radiolabeled thioether peptides for microPET imaging of intestinal inflammation.
Claims Coverage
The independent claim coverage centers on one method for treating or preventing inflammatory bowel disease by administering an effective amount of a peptide dimer compound. The core inventive features are the two peptides with a defined sequence, the thioether bond between 2-methylbenzoyl and Pen, and the linker moiety connecting the two peptides. Dependent refinements further specify attachment to D-Lys, a diglycolic acid linker, acetate salt form, oral administration, and narrowing to Crohn’s disease.
Treating or preventing inflammatory bowel disease with a peptide dimer compound
Providing to a subject in need thereof an effective amount of a peptide dimer compound comprising two peptides, or a pharmaceutically acceptable salt thereof.
Thioether-bonded 2-methylbenzoyl to Pen within each peptide
Each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen as part of the defined peptide sequence.
Linking two peptides by a linker moiety
The two peptides are linked by a linker moiety, forming the peptide dimer compound.
Linker moiety bound to D-Lys
The linker moiety is bound to the D-Lys of each of the two peptides.
Diglycolic acid linker moiety
The linker moiety is diglycolic acid (DIG).
Acetate salt presentation
The peptide dimer compound, or a pharmaceutically acceptable salt, is provided as an acetate salt.
Oral administration
The peptide molecule is orally administered as part of the method.
Crohn’s disease indication
The method is for treating inflammatory bowel disease specifically Crohn’s disease.
The claim coverage is directed to administering a peptide dimer containing two defined thioether-bearing peptides, a thioether bond between 2-methylbenzoyl and Pen, and a linker moiety connecting the two peptides. The remaining claim refinements specify attachment to D-Lys, a diglycolic acid linker, acetate salt form, oral administration, and Crohn’s disease.
Stated Advantages
Improved binding potency/selectivity to α4β27 integrin versus α4β21.
Improved gastrointestinal stability in simulated intestinal fluid and simulated gastric fluid under reduced conditions (DTT).
Redox stability.
Antagonizes integrin α4β27 by inhibiting α4β27 binding to MAdCAM in vivo.
Orally stable, chelated/radiolabeled thioether peptides for microPET imaging of intestinal inflammation.
Documented Applications
Treating or preventing inflammatory bowel disease (IBD) in a subject, including Crohn’s disease and ulcerative colitis.
MicroPET imaging of intestinal inflammation using orally stable, chelated/radiolabeled thioether peptides.
Oral delivery of the therapeutic composition.
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