WO2011071927A2 - Traitement des troubles gastro-intestinaux - Google Patents

Traitement des troubles gastro-intestinaux Download PDF

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Publication number
WO2011071927A2
WO2011071927A2 PCT/US2010/059294 US2010059294W WO2011071927A2 WO 2011071927 A2 WO2011071927 A2 WO 2011071927A2 US 2010059294 W US2010059294 W US 2010059294W WO 2011071927 A2 WO2011071927 A2 WO 2011071927A2
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WIPO (PCT)
Prior art keywords
cys
asp
seq
glu
tyr
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PCT/US2010/059294
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English (en)
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WO2011071927A3 (fr
Inventor
Mark G. Currie
Daniel P. Zimmer
Angelika Fretzen
Marco Kessler
Brian M. Cali
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Ironwood Pharmaceuticals, Inc.
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Application filed by Ironwood Pharmaceuticals, Inc. filed Critical Ironwood Pharmaceuticals, Inc.
Priority to JP2012543205A priority Critical patent/JP5984675B2/ja
Priority to EP10795838.1A priority patent/EP2509992B1/fr
Priority to RU2012128509/04A priority patent/RU2012128509A/ru
Priority to US13/514,158 priority patent/US8735360B2/en
Priority to CN201080063196.9A priority patent/CN102822194B/zh
Publication of WO2011071927A2 publication Critical patent/WO2011071927A2/fr
Publication of WO2011071927A3 publication Critical patent/WO2011071927A3/fr
Priority to US14/286,145 priority patent/US20140256634A1/en
Priority to US14/589,213 priority patent/US20150119328A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to peptides, compositions and methods for treating upper gastrointestinal disorders.
  • FD and GP are upper gastrointestinal (GI) disorders that are collectively characterized by symptoms that include bloating, epigastric (upper abdominal) pain and/or burning, nausea, vomiting and early satiation.
  • Therapeutic options for FD and GP patients are extremely limited, due to both lack of efficacy and poor safety profiles for existing therapies.
  • Dyspepsia is defined as the presence of one or more dyspepsia symptoms (epigastric pain, burning, bothersome postprandial fullness, and early satiation) that are considered to originate from the gastroduodenal region, in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms (see Drossman, D.A., ed., Rome HI: The
  • FD refers to dyspepsia that has no structural explanation after standard medical investigations, including upper endoscopy.
  • Pathophysiological mechanisms that may be involved in FD include, among others, delayed gastric emptying, impaired gastric accommodation,
  • Dyspepsia is a common syndrome that accounts for about 30% of cases seen by
  • GP refers to abnormal gastric motility characterized by delayed gastric emptying in the absence of mechanical obstruction.
  • GP may be idiopathic or may be caused by various conditions, including Type I or Type ⁇ diabetes mellitus, viral infection, scleroderma, nervous system disorders such as Parkinson's disease, metabolic disorders such as hypothyroidism, postoperative ileus, and certain medications, including narcotic pain medications, tricyclic antidepressants and calcium channel blockers.
  • Treatment for cancer, including chemotherapeutic drugs and radiation to the chest and abdomen can also cause gastroparesis, either temporarily or permanently. The most common symptoms are nausea, vomiting, bloating, epigastric pain, weight loss and early satiation.
  • Gastroparesis is a chronic condition that can lead to frequent hospitalization, decreased quality of life, and increased disability and, in severe cases, increased mortality. Severe, symptomatic GP is common in individuals suffering from diabetes, affecting from 5-10% of diabetics for a total patient population of 1 million in the U.S. alone.
  • the present invention features peptides, compositions, and related methods for treating upper gastrointestinal disorders and conditions (e.g., dyspepsia, gastroparesis (GP), postoperative gastric ileus, a functional esophageal disorder, a functional gastroduodenal disorder, gastroesophageal reflux disease (GERD), or a duodenal or stomach ulcer) as well as other conditions and disorders described herein.
  • the compositions feature peptides that activate guanylate cyclase C (GC-C) in the upper GI but activate GC-C in the lower GI much more weakly or not at all.
  • the peptides of the invention are useful because they may alleviate symptoms of upper GI disorders (in whole or in part by increasing upper GI motility and or reducing epigastric pain/discomfort and bloating) without causing pronounced effects in the lower GI tract (e.g., dose-limiting alterations in bowel habits, including diarrhea) at dose levels and dosing frequency sufficient to reduce upper GI symptoms.
  • One aspect of the present inventions provides a peptide comprising the amino acid sequence: Xaai Xaa.2 Xaa-j Xaa* Cyss Xaae Xaa 7 Xaa 8 Cysg Asnio Pron Ala ]2 Cys ]3 Xaai 4 Glyis Xaai 6 Xaan (SEQ ID NO: 1), or a pharmaceutically acceptable salt thereof; wherein
  • Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, ⁇ -carboxylated Asp, Glu, D-Glu, ⁇ -carboxylated Glu, a-aminosuberic acid (Asu), a-aminoadipic acid (Aad), or a-aminopimelic acid (Apm);
  • Xaa 2 is Asp, ⁇ -carboxylated Asp, Glu, ⁇ -carboxylated Glu, Asu, Aad, Apm, or is absent;
  • Xaa 3 is Asp, ⁇ -carboxylated Asp, Glu, ⁇ -carboxylated Glu, Asu, Aad, Apm, or is absent;
  • Xaa* is Cys or D-Cys
  • Xaae is Asp or Glu
  • Xaa 7 is Tyr, Leu, Phe or lie
  • Xaag is Cys or D-Cys
  • Xaau is Thr, Ala or Phe
  • Xaaie is Cys or D-Cys
  • Xaan is Tyr, D-Tyr, or is absent
  • Xaai may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; and if both Xaa 2 and Xaa 3 are absent, then Xaai must be ⁇ -carboxylated Asp or ⁇ - carboxylated Glu, or Xaai must be Asp, D-Asp, Glu, D-Glu, Asu, Aad, or Apm and must be modified on its amino group by ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.
  • a second aspect of the present invention provides pharmaceutical compositions comprising a peptide of the present invention.
  • a third aspect of the present invention provides methods for treating a gastrointestinal disorder, which include administering a pharmaceutical composition according to the present invention.
  • Figure 1 shows the dose response of exemplary peptides of the present invention including Peptide 1 and Peptide 17 in a T84 cell cGMP assay at pH 5 and pH 8.
  • the figure is provided by way of example and is not intended to limit the scope of the present invention.
  • Guanylate cyclase C is a transmembrane receptor that is located on the apical surface of epithelial cells in the stomach and intestine.
  • the receptor has an extracellular ligand- binding domain, a single transmembrane region and a C-terminal guanylyl cyclase domain.
  • the intracellular catalytic domain catalyzes the production of cGMP from GTP.
  • cGMP which is secreted bidirectionally from the epithelium into the mucosa and lumen, has also been shown to dampen afferent C fiber firing, suggesting a potential mechanism for the observed analgesic effects of GC-C agonists on visceral pain.
  • Linaclotide a peptide GC-C agonist that is orally administered and currently in clinical trials for treatment of irritable bowel syndrome with constipation (IBS-c) and chronic constipation (CC), has numerous effects on lower GI physiology including: (1) reduced visceral pain, (2) reduced bloating, and (3) increased GI transit, which can lead to increased stool frequency and improved stool consistency.
  • Orally administered linaclotide acts locally by activating GC-C at the luminal surface; there are no detectable levels of linaclotide seen systemically after oral administration at therapeutic dose levels.
  • the results from clinical trials of linaclotide, as well as preclinical studies that have been done with linaclotide and related peptides suggest that GC-C peptide agonists may be used therapeutically.
  • a GC-C agonist that could be used to alleviate upper GI disorders and symptoms (e.g., functional dyspepsia (FD) and gastroparesis (GP)) without promoting pronounced effects on bowel habits that could result from stimulation of GC-C in lower parts of the GI tract
  • FD functional dyspepsia
  • GP gastroparesis
  • Such a GC-C agonist would decrease the potential for lower GI adverse events, including altered bowel habits and diarrhea.
  • the GC-C peptide agonists described herein are more active in the upper GI tract (e.g., the stomach and duodenum), and less active in the lower GI tract.
  • Such agonists would have benefits in patients who suffer from upper GI disorders (e.g., FD and GP) by (1) reducing visceral pain through cGMP production and or/other mechanisms, (2) decreasing bloating, (3) increasing gastric emptying and/or upper small intestine transit (e.g., duodenal transit), and (4) neutralizing acid in the duodenum by promoting bicarbonate secretion.
  • these agonists by virtue of their targeted activity in the upper GI, would be able to alleviate the symptoms of FD and GP without causing pronounced effects on bowel habits (e.g., that can result from stimulation of GC-C in the lower small intestine).
  • the invention provides novel GC-C peptide agonists useful for the treatment of gastrointestinal disorders, particularly upper GI disorders such as FD and GP.
  • the GC-C peptide agonists described herein have GC-C agonist activity that is pH-dependent.
  • the pH of the GI tract varies along its length in normal, healthy individuals, being lowest in the stomach (pH 1.5-3.5), rising to approximately pH 6 in the upper duodenum and increasing further (pH 7-8) in lower parts of the small intestine. Large intestine pH tends to vary from pH 6 to pH 8.
  • the GC-C agonist peptides described herein are more active at a lower pH and less active at a higher pH.
  • the GC-C agonist peptides are more active in the upper GI, including the esophagus, stomach and upper small intestine (upper duodenum) but are less active as they traverse the rest of the small intestine.
  • Exemplary GC-C agonist peptides described herein exhibit a 10- to 1000-fold decreased potency at pH 8 compared to their potency at pH 5 as determined by in vitro assays that measure ability to bind and/or stimulate GC-C.
  • Some GC-C peptide agonists such as those exemplified in peptides 1 and 2, show little or no pH sensitivity with regard to binding and/or activation of GC-C.
  • the peptides described in the present invention demonstrate that addition of specific N-terminal amino acids render the GC-C peptide agonist activity more sensitive to changes in pH.
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence:
  • Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly, Thr, D- Thr, Asp, D-Asp, ⁇ -carboxylated Asp, Glu, D-Glu, ⁇ -carboxylated Glu, a-aminosuberic acid (Asu), a-aminoadipic acid (Aad), or a-aminopimelic acid (Apm);
  • Xaa 2 is Asp, ⁇ -carboxylated Asp, Glu, ⁇ -carboxylated Glu, Asu, Aad, Apm, or is absent;
  • Xaa 3 is Asp, ⁇ -carboxylated Asp, Glu, ⁇ -carboxylated Glu, Asu, Aad, Apm, or is absent;
  • Xaa 4 is Cys or D-Cys
  • Xaae is Asp or Glu
  • Xaa 7 is Tyr, Leu, Phe or He
  • Xaag is Cys or D-Cys
  • XaaH is Thr, Ala or Phe
  • Xaaie is Cys or D-Cys
  • Xaan is Tyr, D-Tyr, or is absent
  • Xaai may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; and if both Xaa 2 and Xaa 3 are absent, then Xaai must be ⁇ -carboxylated Asp or ⁇ - carboxylated Glu, or Xaai must be Asp, D-Asp, Glu, D-Glu, Asu, Aad, or Apm and must be modified on its amino group by ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.
  • Xaai is modified on its amino group at either or both hydrogen atoms by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.
  • Xaai is not modified on its amino group when either or both of Xaa 2 and Xaa 3 are present
  • Xaa 2 is Asp or Glu. In others, Xaa 2 is Asp.
  • Xaa 2 and Xaa3 are both present.
  • Xaa 2 is present and Xaa 3 is absent In several embodiments, Xaa 2 and Xaa 3 are both absent
  • Xaa 3 is Asp or Glu. In others, Xaa 3 is Asp.
  • Xaa 2 and Xaa 3 are present and Xaai is Asn,
  • Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly,
  • Xaai is Asp, D-Asp, Glu or
  • Xa3 ⁇ 4 is Cys.
  • Xaag is Glu
  • Xaa 7 is Tyr or Leu.
  • Xaa 8 is Cys.
  • Xaa )4 is Thr.
  • Xaaie is Cys.
  • Xaan is Tyr
  • Xaa ]7 is absent.
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein said peptide comprises the amino acid sequence Xaai Xaa 2 Xaa 3 Cys4 Cyss Glue Xaa 7 Cys g Cys 9 Asnio Pron Ala t2 Cys Thru Glyi 5 Cysi 6 Xaa n (SEQ ID NO:2); wherein
  • Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly, Thr, D- Thr, Asp, D-Asp, Glu or D-Glu;
  • Xaa 2 is Asp or Glu
  • Xaa 3 is Asp, Glu, or is absent;
  • Xaa 7 is Tyr or Leu
  • Xaan is Tyr or is absent
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein said peptide comprises:
  • the C-terminal amino acid residue may be an L-amino acid residue or a D-amino acid residue and if the N-terminal amino acid residue is Asn, Asp, Ala, Pro, Thr or Glu, the N- terminal residue may be an L-amino acid residue or a D-amino acid residue.
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein said peptide comprises: D-Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ED NO:47); D-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:48); D-Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ED NO:49); D-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ED NO:50); Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys D-Tyr (SEQ ED NO:51); D-Asp Asp Asp Cys Cys
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence
  • Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly, Thr, D- Thr, Asp, D-Asp, Glu, or D-Glu;
  • Xaa 3 is Asp or is absent
  • Xaa 7 is Tyr or Leu
  • Xaan is Tyr or is absent
  • the peptide comprises the amino acid sequence:
  • the C-terminal amino acid residue may be an L-amino acid residue or a D-amino acid residue and if the N-terminal amino acid residue is Asn, Asp, Ala, Pro, Thr or Glu, the N- terminal residue may be an L-amino acid residue or a D-amino acid residue.
  • the peptide comprises no more than 50, 40, 30 or 20 amino acids.
  • the peptide comprises no more than 19, 18, 17 or 16 amino acids.
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid sequence:
  • Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly, Thr, D- Thr, Asp, D-Asp, ⁇ -carboxylated Asp, Glu, D-Glu, ⁇ -carboxylated Glu, a-aminosuberic acid (Asu), a-aminoadipic acid (Aad), or a-aminopimelic acid (Apm);
  • Xaa2 is Asp, ⁇ -carboxylated Asp, Glu, ⁇ -carboxylated Glu, Asu, Aad, Apm, or is absent;
  • Xaa 3 is Asp, ⁇ -carboxylated Asp, Glu, ⁇ -carboxylated Glu, Asu, Aad, Apm, or is absent;
  • Xaa 4 is Cys or D-Cys
  • Xaae is Asp or Glu
  • Xaa 7 is Tyr, Leu, Phe or lie
  • Xaae is Cys or D-Cys
  • Xaan is Thr, Ala or Phe
  • Xaaie is Cys or D-Cys
  • Xaan is Tyr, D-Tyr, or is absent
  • Xaai may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; and if both Xaa 2 and Xaa 3 are absent, then Xaai must be ⁇ -carboxylated Asp or ⁇ - carboxylated Glu, or Xaai must be Asp, D-Asp, Glu, D-Glu, Asu, Aad, Apm and must be modified on its amino group by ethanedioic acid, propanedioic acid, or butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.
  • Xaa 2 is Asp or Glu. In others, Xaa 2 is Asp. [00039] In several embodiments, Xaa 2 and Xaa 3 are both present. In several embodiments, Xaa 2 is present and Xaa 3 is absent In several embodiments, Xaa 2 and Xaa 3 are both absent [00040] In several embcidiments, Xaa 3 is Asp or Glu. In others, Xaa 3 is Asp.
  • Xaa 2 and Xaa are present and Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, ⁇ - carboxylated Asp, Glu, D-Glu, ⁇ -carboxylated Glu, Asu, Aad or Apm.
  • Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu.
  • Xaai is Asp, D-Asp, Glu or D-Glu.
  • Xaa 4 is Cys.
  • Xaa ⁇ is Glu
  • Xaa 7 is Tyr or Leu.
  • Xaag is Cys.
  • Xaa ⁇ is Thr.
  • Xaaie is Cys.
  • Xaan is Tyr
  • Xaan is absent
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein said peptide consists of the amino acid sequence Xaai Xaa 2 Xaa 3 Cys 4 Cys 5 Glue Xaa 7 Cys 8 Cys 9 Asnio Pro n Ala )2 Cysi 3 Thri 4 Glyi 5 Cysi 6 Xaa n (SEQ ID NO:2); wherein
  • Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly, Thr, D- Thr, Asp, D-Asp, Glu or D-Glu;
  • Xaa 2 is Asp or Glu
  • Xaa 3 is Asp, Glu, or is absent;
  • Xaa is Tyr or Leu
  • Xaan is Tyr or is absent.
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein said peptide consists of:
  • the C-terminal amino acid residue may be an L-amino acid residue or a D-amino acid residue and if the N-terminal amino acid residue is Asn, Asp, Ala, Pro, Thr or Glu, the N- terminal residue may be an L-amino acid residue or a D-amino acid residue.
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein said peptide consists of:
  • the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid sequence
  • Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, ⁇ -Ala, D-Ala, Val, D-Val, Gly, Thr, D- Thr, Asp, D-Asp, Glu, or D-Glu;
  • Xaa 3 is Asp or is absent
  • Xaa 7 is Tyr or Leu
  • Xaan is Tyr or is absent.
  • the peptide consists of the amino acid sequence:
  • the C-terminal amino acid residue may be an L-amino acid residue or a D-amino acid residue and if the N-terminal amino acid residue is Asn, Asp, Ala, Pro, Thr or Glu, the N- terminal residue may be an L-amino acid residue or a D-amino acid residue.
  • the peptide is isolated. In others, the peptide is purified.
  • a pharmaceutically acceptable salt of the peptide is provided.
  • the pharmaceutically acceptable salt is a chloride salt.
  • one or both members of one or both pairs of Cys residues which normally form a disulfide bond can be replaced by homocysteine, penicillamine, 3- mercaptoproline (Kolodziej et al. 1 96 Int J Pept Protein Res 48:274); ⁇ , ⁇ -dimethylcysteine (Hunt et al. 1993 Int J Pept Protein Res 42:249) or diaminopropionic acid (Smith et al. 1978 J Med Chem 21: 117) to form alternative internal cross-links at the positions of the normal disulfide bonds.
  • the disulfide bonds may be replaced by hydrocarbon crosslinking (Schafmeister et al. 2000 J Am Chem Soc 122:5891, Patgjri et al. 2008 Acc Chem Res 41:1289, Henchey et al. 2008 Curr Opin Chem Biol 12:692).
  • peptides or precursor peptides of the invention can be produced recombinantly in any known protein expression system, including, without limitation, bacteria (e.g., E. coli or Bacillus subtilis), insect cell systems (e.g., Drosophila Sf9 cell systems), yeast cell systems (e.g., S. cerevisiae, S. saccharomyces) or filamentous fungal expression systems, or animal cell expression systems (e.g., mammalian cell expression systems). Peptides or precursor peptides of the invention may also be chemically synthesized.
  • bacteria e.g., E. coli or Bacillus subtilis
  • insect cell systems e.g., Drosophila Sf9 cell systems
  • yeast cell systems e.g., S. cerevisiae, S. saccharomyces
  • filamentous fungal expression systems e.g., cowpomyces
  • animal cell expression systems e.g., mammalian cell expression systems.
  • the nucleic acid molecule encoding the peptide may also encode a leader sequence that permits the secretion of the mature peptide from the cell.
  • the sequence encoding the peptide can include the pre sequence and the pro sequence of, for example, a naturally occurring bacterial ST peptide.
  • the secreted, mature peptide can be purified from the culture medium.
  • the sequence encoding a peptide described herein is can be inserted into a vector capable of delivering and maintaining the nucleic acid molecule in a bacterial cell.
  • the DNA molecule may be inserted into an autonomously replicating vector (suitable vectors include, for example, pGEM3Z and pcDNA3, and derivatives thereof).
  • the vector nucleic acid may be a bacterial or bacteriophage DNA such as bacteriophage lambda or M13 and derivatives thereof. Construction of a vector containing a nucleic acid described herein can be followed by transformation of a host cell such as a bacterium. Suitable bacterial hosts include but are not limited to, E. coli, B.
  • the genetic construct also includes, in addition to the encoding nucleic acid molecule, elements that allow expression, such as a promoter and regulatory sequences.
  • the expression vectors may contain transcriptional control sequences that control transcriptional initiation, such as promoter, enhancer, operator, and repressor sequences. A variety of transcriptional control sequences are well known to those in the art.
  • the expression vector can also include a translation regulatory sequence (e.g., an untranslated 5' sequence, an untranslated 3' sequence, or an internal ribosome entry site).
  • the vector can be capable of autonomous replication or it can integrate into host DNA to ensure stability during peptide production.
  • the protein coding sequence that includes a peptide described herein can also be fused to a nucleic acid encoding a peptide affinity tag, e.g., glutathione S-transferase (GST), maltose E binding protein, protein A, FLAG tag, hexa-histidine, myc tag or the influenza HA tag, in order to facilitate purification.
  • GST glutathione S-transferase
  • the affinity tag or reporter fusion joins the reading frame of the peptide of interest to the reading frame of the gene encoding the affinity tag such that a translational fusion is generated. Expression of the fusion gene results in translation of a single peptide that includes both the peptide of interest and the affinity tag.
  • DNA sequence encoding a protease recognition site will be fused between the reading frames for the affinity tag and the peptide of interest.
  • peptides containing amino acids not normally incorporated by the translation machinery and described above may be recombinandy produced by tRNA modification methods.
  • Methods for modifying tRNA including, but not limited to, modifying the anti-codon, the amino acid attachment site, and or the accepter stem to allow incorporation of unnatural and/or arbitrary amino acids are known in the art (Biochem. Biophys. Res. Comm. (2008) 372: 480-485; Chem. Biol. (2009) 16:323-36; Nat. Methods (2007) 4:239-44; Nat. Rev. Mol.
  • peptides may be chemically produced.
  • Peptides can be synthesized by a number of different methods including solution and solid phase synthesis using traditional BOC or FMOC protection.
  • the peptide can be synthesized on 2- Chlorotrityl or Wang resin using consecutive amino acid couplings.
  • the following protecting groups can be used: Fluorenylmethyloxycarbonyl or torf-butyloxycarbonyl (alpha-amino groups, N-terminus); trityl or terf-butyl (thiol groups of Cys); tert-butyl ( ⁇ -carboxyl of glutamic acid and the hydroxyl group of threonine, if present); and trityl ( ⁇ -amid function of the asparagine side chain and the phenolic group of tyrosine, if present).
  • Coupling can be effected with DIC and HOBt in the presence of a tertiary amine, and the peptide can be deprotected and cleaved from the solid support using cocktail (trifluoroacetic acid 81%, phenol 5%, thioanisole 5%, 1,2- ethanedithiol 2.5%, water 3%, dimethylsulphide 2%, ammonium iodide 1.5% w/w). After removal of trifluoroacetic acid and other volatiles the peptide can be precipitated using an organic solvent Disulfide bonds between Cys residues can be formed using dimethyl sulfoxide (Tam et al. (1991) /. Am. Chem. Soc. 113:6657-62) or using an air oxidation strategy. The resulting peptide can be purified by reverse-phase chromatography and lyophilized.
  • cocktail trifluoroacetic acid 81%, phenol 5%, thioanisole 5%, 1,2- e
  • Peptides can be made, isolated or used either in form of the base or as
  • salts include, without limitation, acetate, chloride, sulfate and phosphate salts of the peptide.
  • compositions of peptides and GC-C receptor agonists Compositions of peptides and GC-C receptor agonists
  • compositions wherein the peptides, alone or in combination, can be combined with any pharmaceutically acceptable carrier or medium.
  • the peptides can be combined with materials that do not produce an adverse, allergic or otherwise unwanted reaction when administered to a patient.
  • the carriers or media used can include solvents, dispersants, coatings, absorption promoting agents, controlled release agents, and one or more inert excipients (which include starches, polyols, granulating agents, microfine cellulose, macrocrystalline cellulose (e.g., celphere, Celphere beads®), diluents, lubricants, binders, disintegrating agents, and the like), etc.
  • tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques.
  • excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, disintegrants, lubricants, anti-microbial agents, and coating agents.
  • binder refers to any pharmaceutically acceptable binder that may be used in the practice of the invention.
  • pharmaceutically acceptable binders include, without limitation, a starch (e.g., corn starch, potato starch and pre-gelatinized starch (e.g., STARCH 1500® and STARCH 1500 LM®, sold by Colorcon, Ltd.) and other starches), maltodextnn, gelatin, natural and synthetic gums such as acacia, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose (hypromellose), ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, carboxymethylcellulose, powdered cellulose, microfine cellulose, microcrystalline cellulose (e.g., AV
  • binders examples include polyvinyl alcohol, polyvinylpyrrolidone (povidone), a starch, maltodextrin or a cellulose ether (such as, for example, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose).
  • a cellulose ether such as, for example, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • filler refers to any pharmaceutically acceptable filler that may be used in the practice of the invention.
  • pharmaceutically acceptable fillers include, without limitation, talc, calcium carbonate (e.g., granules or powder), dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate (e.g., granules or powder),
  • microcrystalline cellulose e.g., Avicel PH101 or Celphere CP-305
  • microfine cellulose powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch (e.g., Starch 1500), pre-gelatinized starch, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, isomalt, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, xylitol, myoinositol, and mixtures thereof.
  • starch e.g., Starch 1500
  • pre-gelatinized starch lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, isomalt, raffinose, maltitol, melezitose, stachyos
  • Examples of pharmaceutically acceptable fillers that may be particularly used for coating the peptides include, without limitation, talc, microcrystalline cellulose (e.g., Avicel PH101 or Celphere CP-305), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, isomalt, dibasic calcium phosphate, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, xylitol, mannitol, myoinositol, and mixtures thereof.
  • microcrystalline cellulose e.g., Avicel PH101 or Celphere CP-305
  • powdered cellulose dextrates
  • kaolin e.g., kaolin
  • additives refers to any pharmaceutically acceptable additive.
  • Pharmaceutically acceptable additives include, without limitation, disintegrants, dispersing additives, lubricants, glidants, antioxidants, coating additives, diluents, surfactants, flavoring additives, humectants, absorption promoting additives, controlled release additives, anti-caking additives, anti-microbial agents (e.g., preservatives), colorants, desiccants, plasticizers and dyes.
  • an “excipient” is any pharmaceutically acceptable additive, filler, binder or agent.
  • compositions of the present invention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, glidants, anti-adherents, anti-static agents, surfactants (wetting agents), antioxidants, film-coating agents, and the like. Any such optional ingredient must be compatible with the compound described herein to insure the stability of the formulation.
  • the composition may contain other additives as needed, including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.
  • additives including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino
  • compositions can include, for example, various additional solvents, dispersants, coatings, absorption promoting additives, controlled release additives, and one or more inert additives (which include, for example, starches, polyols, granulating additives, microcrystalline cellulose, diluents, lubricants, binders, disintegrating additives, and the like), etc. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or non-aqueous techniques.
  • Compositions can also include, for example, anti-caking additives, preservatives, sweetening additives, colorants, flavors, desiccants, plasticizers, dyes, and the like.
  • Suitable disintegrants include, for example, agar-agar, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, povidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Suitable lubricants include, for example, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, syloid silica gel (AEROSIL 200, W.R.
  • AEROSIL 200 ethyl oleate
  • W.R syloid silica gel
  • Suitable glidants include, for example, leucine, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • Suitable anti-caking additives include, for example, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, and mixtures thereof.
  • Suitable anti-microbial additives that may be used, e.g., as a preservative for the peptides compositions, include, for example, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, cresol, chlorobutanol, dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenoxyethanol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimersol, thymo, and mixtures thereof.
  • Suitable antioxidants include, for example, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, propyl gallate, ascorbic acid and salts or esters thereof, tocopherol and esters thereof, alpha-lipoic acid and beta-carotene.
  • Suitable coating additives include, for example, sodium carboxymethyl cellulose, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose phthalate, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, and mixtures thereof.
  • Suitable protective coatings include Aquacoat (e.g., Aquacoat Ethylcellulose Aquaeous Dispersion, 15% w/w, FMC
  • Biopolymer ECD-30
  • Eudragit e.g., Eudragit E PO PE-EL, Roehm Pharma Polymers
  • Opadry e.g., Opadry AMB dispersion, 20% w/w, Colorcon.
  • suitable additives for the peptides composition include one or more of sucrose, talc, magnesium stearate, crospovidone or BHA.
  • compositions of the present invention can also include other excipients, agents, and categories thereof including but not limited to L-histidine, Pluronic®, Poloxamers (such as Lutrol® and Poloxamer 188), ascorbic acid, glutathione, permeability enhancers (e.g., lipids, sodium cholate, acylcarnitine, salicylates, mixed bile salts, fatty acid micelles, chelators, fatty acid, surfactants, medium chain glycerides), protease inhibitors (e.g., soybean trypsin inhibitor, organic acids), pH-lowering agents and absorption enhancers effective to promote bioavailability (including but not limited to those described in US Pat. Nos.
  • L-histidine Pluronic®
  • Poloxamers such as Lutrol® and Poloxamer 188
  • ascorbic acid glutathione
  • permeability enhancers e.g., lipids, sodium cholate, acylcarnitine
  • materials for chewable tablets like dextrose, fructose, lactose monohydrate, lactose and aspartame, lactose and cellulose, maltodextrin, maltose, mannitol, microcrystalline cellulose and guar gum, sorbitol crystalline); parenterals (like mannitol and povidone); plasticizers (like dibutyl sebacate, plasticizers for coatings, polyvinylacetate phthalate); powder lubricants (like glyceryl behenate); soft gelatin capsules (like sorbitol special solution); spheres for coating (like sugar spheres); spheronization agents (like glyceryl behenate and microcrystalline cellulose); suspending/gelling agents (like carrageenan, gellan gum, mannitol, microcrystalline cellulose, povidone, sodium starch glycolate, xanthan gum); sweeteners (like aspartame, as
  • FD&C Yellow No.10 glycerol palmitostearate, glyceryl monostearate, indigo carmine, lecithin, mannitol, methyl and propyl parabens, mono ammonium glycyrrhizinate, natural and artificial orange flavor, pharmaceutical glaze, poloxamer 188, Polydextrose, polysorbate 20, polysorbate 80, polyvidone, pregelatinized corn starch, pregelatinized starch, red iron oxide, saccharin sodium, sodium carboxymethyl ether, sodium chloride, sodium citrate, sodium phosphate, strawberry flavor, synthetic black iron oxide, synthetic red iron oxide, titanium dioxide, and white wax.
  • a pharmaceutical composition comprising a peptide described herein and one or more stabilizing agents selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K*. Na + or Al , a combination thereof, and/or a sterically hindered primary amine.
  • the agent is Mg + , Ca + or Zn 2+ or a combination thereof.
  • the cation is provided, without limitation, as magnesium acetate, magnesium chloride, magnesium phosphate, magnesium sulfate, calcium acetate, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, zinc chloride, zinc phosphate, zinc sulfate, manganese acetate, manganese chloride, manganese phosphate, manganese sulfate, potassium acetate, potassium chloride, potassium phosphate, potassium sulfate, sodium acetate, sodium chloride, sodium phosphate, sodium sulfate, aluminum acetate, aluminum chloride, aluminum phosphate or aluminum sulfate.
  • the cation is provided as magnesium chloride, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, manganese chloride, potassium chloride, sodium chloride or aluminum chloride. In other embodiments, the cation is provided as calcium chloride, magnesium chloride or zinc acetate.
  • the stabilizing agent is a stencally hindered primary amine. In a further embodiment, the stencally hindered primary amine is an amino acid. In yet a further embodiment, the amino acid is a naturally occurring amino acid.
  • the naturally occurring amino acid is selected from the group consisting of: histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan, glycine and valine; yet further, the naturally- occurring amino acid is leucine, isoleucine, alanine or methionine. In a still further embodiment, the naturally-occurring amino acid is leucine.
  • the sterically hindered primary amine is a non-naturally occurring amino acid (e.g., 1-aminocyclohexane carboxylic acid, lanthanine, or theanine).
  • the sterically hindered primary amine is cyclohexylamine, 2-methylbutylamine or a polymeric amine such as chitosan.
  • one or more sterically hindered primary amines may be used in a composition.
  • the sterically hindered primary amine has the formula:
  • Rj, R 2 and R 3 are independently selected from: H, C(0)OH, C1-C6 alkyl, Q-Ce alkylether, Ci-Ce alkylthioether, Ci-Ce alkyl carboxylic acid, Ci-Ce alkyl carboxylamide and alkylaryl, wherein any group can be singly or multiply substituted with: halogen or amino, and provided that no more than two of Ri, R2 and R3 are H. In another embodiment, no more than one of Ri, R 2 and R3 is H.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, peptide, a cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K*, Na + or Al 3 *, or a mixture thereof, and a sterically hindered primary amine.
  • the cation is Mg + , Ca 2+ or Zn 2+ or a mixture thereof.
  • the cation is Mg + , Ca 2+ or Zn 2+ or a mixture thereof.
  • composition further comprises a pharmaceutically acceptable binder and/or a pharmaceutically acceptable glidant, lubricant or additive that acts as both a glidant and lubricant and/or an antioxidant
  • the pharmaceutical composition is applied to a carrier.
  • the carrier is a filler.
  • the molar ratio of cation : sterically hindered primary amine : peptide in the aqueous solution applied to the carrier is 5-100:5-50:1. In some cases, the molar ratio of cation:sterically hindered primary amine may be equal to or greater than 2: 1 (e.g., between 5:1 and 2:1).
  • the molar ratio of cation: sterically hindered primary amine: peptide applied to the carrier is 100:50:1, 100:30:1, 80:40:1, 80:30:1, 80:20:1, 60:30:1, 60:20:1, 50:30:1, 50:20:1, 40:20:1, 20:20:1, 10:10:1, 10:5:1 or 5:10:1.
  • binder e.g.,
  • methylcellulose is present in the GC-C agonist peptide solution applied to the carrier it can be present at 0.5%-2.5% by weight (e.g., 0.7%-1.7% or 0.7%-l%, 1.5%, or 0.7%).
  • the pharmaceutical composition further comprises a pharmaceutically acceptable binder or additive, and/or a pharmaceutically acceptable glidant, lubricant or additive that acts as both a glidant and lubricant and/or an antioxidant.
  • Suitable pharmaceutical compositions in accordance with the invention will generally include an amount of the active compound(s) with an acceptable pharmaceutical diluent or excipient, such as a sterile aqueous solution, to give a range of final concentrations, depending on the intended use.
  • an acceptable pharmaceutical diluent or excipient such as a sterile aqueous solution.
  • the techniques of preparation are generally well known in the art, as exemplified by Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Company, 1995).
  • the peptides described herein are preferably administered orally, e.g., as a tablet, capsule, sachet containing a predetermined amount of the active ingredient pellet, gel, paste, syrup, bolus, electuary, slurry, powder, lyophilized powder, granules, as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a liposomal formulation (see, e.g., EP 736299) or in some other form.
  • a liposomal formulation see, e.g., EP 736299
  • Orally administered compositions can include binders, lubricants, inert diluents, lubricating, surface active or dispersing agents, flavoring agents, and humectants.
  • Orally administered formulations such as tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the peptides can be coadministered with other agents used to treat gastrointestinal disorders including but not limited to the agents described herein.
  • suitable pharmaceutical compositions may comprise one or more other therapeutic agents.
  • therapeutic agents include, without limitation, analgesic agents; anti-secretory agents, including proton pump inhibitors, acid pump antagonists, H2 receptor antagonists; PDE5 inhibitors; GABA-B antagonists; bile acid sequestrants; prokinetic and promotility agents; antidepressants; antibiotics; antiemetics; and mucosal-protecting agents.
  • a method of treatment is provided for gastrointestinal disorders.
  • the gastrointestinal disorder is an upper GI disorder.
  • the disorder is GP, post-operative gastric ileus, a functional esophageal disorder, a functional gastroduodenal disorder, gastroesophageal reflux disease (GERD), celiac disease, mucositis, or a duodenal or stomach ulcer.
  • GFD gastroesophageal reflux disease
  • the gastrointestinal disorder is GP.
  • the GP is idiopathic, diabetic or post-surgical GP.
  • the gastrointestinal disorder is post-operative gastric ileus.
  • the gastrointestinal disorder is a functional esophageal disorder.
  • the functional esophageal disorder is functional heartburn, functional chest pain of presumed esophageal origin, functional dysphagia or globus.
  • the gastrointestinal disorder is a functional gastroduodenal disorder.
  • the functional gastroduodenal disorder is FD, a belching disorder, a nausea or vomiting disorder, or rumination syndrome.
  • the functional gastroduodenal disorder is FD.
  • the FD is postprandial distress syndrome or epigastric pain syndrome.
  • the belching disorder is aerophagia or unspecified excessive belching.
  • the nausea or vomiting disorder is chronic idiopathic nausea, functional vomiting or cyclic vomiting syndrome.
  • the gastrointestinal disorder is gastroesophageal reflux disease (GERD).
  • GEF gastroesophageal reflux disease
  • the gastrointestinal disorder is celiac disease.
  • the gastrointestinal disorder is mucositis.
  • the gastrointestinal disorder is a duodenal or stomach ulcer.
  • peptides and agonists described herein can be used alone or in combination therapy for the treatment, prevention or reduction of visceral pain associated with a
  • the GC-C receptor agonists described herein can be administered in combination with other agents.
  • the peptides can be administered with an analgesic peptide or compound.
  • the analgesic peptide or compound can be covalently attached to a peptide described herein or it can be a separate agent that is administered together with or sequentially with a peptide described herein in a combination therapy.
  • GC-C receptor agonists described herein may also be administered in combination with other agents used to treat upper GI disorders including antidepressants, promotility or prokinetic agents, antiemetics, antibiotics, proton pump inhibitors, acid blockers (e.g., histamine H2 receptor antagonists), acid pump antagonists, PDES inhibitors, GABA-B agonists, bile acid sequestrants, and mucosal protecting agents.
  • agents used to treat upper GI disorders including antidepressants, promotility or prokinetic agents, antiemetics, antibiotics, proton pump inhibitors, acid blockers (e.g., histamine H2 receptor antagonists), acid pump antagonists, PDES inhibitors, GABA-B agonists, bile acid sequestrants, and mucosal protecting agents.
  • agents used to treat upper GI disorders including antidepressants, promotility or prokinetic agents, antiemetics, antibiotics, proton pump inhibitors, acid blockers (e.g., histamine H2 receptor antagonists
  • useful analgesic agents that may be used with the peptides described herein include Ca channel blockers (e.g., ziconotide), 5HT receptor antagonists (e.g., 5HT3, 5HT4 and 5HT1 receptor antagonists), 5HT4 agonists (e.g., tegaserod [Zelnorm®], mosapride, zacopride, cisapride, renzapride, prucalopride [Resolor®], benzimidazolone derivatives such as BIMU 1 and BIMU 8, and firexapride), 5HT1 agonists (e.g., sumatriptan and buspirone), opioid receptor agonists (e.g., loperamide, fedotozine, enkephalin pentapeptide, morphine, diphenyloxylate, frakefamide, trimebutine and fentanyl), CC receptor agonists (e.g.,
  • one or more other therapeutic agents may be used in combination with the peptides described herein.
  • agents include antidepressants, promotility or prokinetic agents, antiemetics, antibiotics, proton pump inhibitors, acid blockers (e.g., histamine H2 receptor antagonists), acid pump antagonists, PDE5 inhibitors, GABA-B agonists, bile acid sequestrants, and mucosal protecting agents.
  • antidepressants include, without limitation, tricyclic antidepressants such as amitriptyline (Elavil®), desipramine (Norpramin®), imipramine (Tofranil®), amoxapine (Asendin®), nortriptyline; the selective serotonin reuptake inhibitors (SSRI's) such as paroxetine (Paxil®), fluoxetine (Prozac®), sertraline (Zoloft®), and citralopram (Celexa®); and others such as doxepin (Sinequan®) and trazodone (Desyrel®).
  • tricyclic antidepressants such as amitriptyline (Elavil®), desipramine (Norpramin®), imipramine (Tofranil®), amoxapine (Asendin®), nortriptyline
  • SSRI's selective serotonin reuptake inhibitors
  • Paxil® paroxetine
  • promotility and prokinetic agents include, without limitation, itopride, octreotide, bethanechol, metoclopramide (Reglan®), domperidone (Motilium®), erythromycin (and derivatives thereof) and cisapride (Propulsid®).
  • An example of antiemetics includes, without limitation, prochlorperazine.
  • antibiotics examples include those that may be used to treat Heliobacter pylori infections, such as amoxicillin, tetracycline, metronidazole, or clarithromycin. Other antibiotics such as erythromycin and derivatives thereof may also be used in combination with the peptides described herein.
  • Examples of proton pump inhibitors include, without limitation, omeprazole (Prilosec®), esomeprazole (Nexium®), lansoprazole (Prevacid®), pantoprazole (Protonix®) and rabeprazole (Aciphex®).
  • Examples of H2 receptor blockers include, without limitation, including cimetidine, ranitidine, famotidine and nizatidine.
  • Examples of acid pump antagonists include, without limitation, revaprazan, CS-526 (/. Pharmacol Exp. Ther. (2007) 323:308-317), PF-03716556 (J. Pharmacol. Exp. Ther. (2009) 328(2):671-9), and YH1885 (Drug Metab.
  • Examples of PDE5 inhibitors include, without limitation, avanafil, lodenafil, mirodenafil, sildenafil citrate, tadalafil, vardenafil and udenafil.
  • GABA-B agonists include, without limitation, baclofen and XP19986 (CAS Registry No. 847353-30-4).
  • Examples of bile acid sequestrants include, without limitation, GT102-279, cholestyramine, colesevelam, colesevelam hydrochloride, ursodeoxycholic acid, colestipol, colestilan, sevelamer,
  • mucosal protecting agents include, without limitation, sucralfate (Carafate), teprenone, polaprezinc, cetraxate and bismuth subsalicyclate.
  • Combination therapy can be achieved by administering two or more agents, e.g., a GC-C receptor agonist described herein and another therapeutic peptide or compound, each of which is formulated and administered separately, or by administering two or more agents in a single formulation.
  • agents e.g., a GC-C receptor agonist described herein and another therapeutic peptide or compound, each of which is formulated and administered separately, or by administering two or more agents in a single formulation.
  • Other combinations are also encompassed by combination therapy.
  • two agents can be formulated together and administered in conjunction with a separate formulation containing a third agent. While the two or more agents in the combination therapy can be administered simultaneously, they need not be.
  • administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, IS, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.
  • the dose range for adult humans may be generally from 5
  • Tablets, capsules, or other forms of presentation provided in discrete units may conveniently contain an amount of compound described herein that is effective at such dosage or as a multiple of the same, for instance, units containing 25 ug to 2 mg or around 100 ug to 1 mg.
  • the precise amount of compound prescribed to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
  • the dosage unit is administered with food at any time of the day, without food at any time of the day, with food after an overnight fast (e.g., with breakfast), at bedtime after a low fat snack.
  • the dosage unit is administered prior to or subsequent to food consumption (e.g., a meal).
  • the dosage unit is administered approximately 15 minutes to 1 hour prior to food consumption.
  • the dosage unit is administered once a day, twice a day, three times a day, four times a day, five times a day or six times a day. In certain embodiments the dosage unit and daily dose are equivalent
  • the precise amount of each of the two or more active ingredients in a dosage unit will depend on the desired dosage of each component
  • a dosage schedule e.g., a dosage schedule specifying a certain number of units and a particular timing for administration
  • deliver the same dosage of each component as would be administered if the patient was being treated with only a single component.
  • the pharmaceutical composition can include additional ingredients including but not limited to the active ingredients and excipients described herein.
  • one or more therapeutic agents of the dosage unit may exist in an extended or control release formulation and additional therapeutic agents may not exist in extended release formulation.
  • a peptide or agonist described herein may exist in a controlled release formulation or extended release formulation in the same dosage unit with another agent that may or may not be in either a controlled release or extended release formulation.
  • GC-C agonist peptides or pharmaceutically acceptable salts thereof as described herein were prepared by solid phase chemical synthesis and natural folding (air oxidation) by American Peptide Company (Sunnyvale, CA).
  • the peptides and their sequences are shown below (wherein the amino acid sequence is the standard one letter code and "dD" refers to D- Asp, "dA” refers to D-Ala, “dY” refers to D-Tyr, “dN” refers to D-Asn and " ⁇ " refers to beta- Ala): Peptide Name Amino Acid Sequence m
  • Peptide 15 PADDCCELCCNPACTGCY (SEQ ID NO: 61)
  • Example 1 cGMP accumulation in T84 cells for analysis of GC-C activity
  • cGMP accumulation in T84 cells was analyzed for GC-C activity.
  • cGMP assay 4.5 x 10 s cells/mL of T84 cells were grown overnight in 24- well tissue culture plates. On the next day, the T84 cells were washed twice with 1 mL of DMEM + 20 mM MES (pH 5) or DMEM + 50 mM sodium bicarbonate (NaBicarb, pH 8) in which these buffers did not contain serum. After the second wash, the cells were incubated with 450 ⁇ of 1 mM
  • the peptides were then diluted in either pH 5 or pH 8 buffer to a 1 Ox concentration.
  • the peptide solution of 50 ⁇ iL was diluted to a final volume of 500 ⁇ - with the T84 cells, bringing each peptide concentration to lx.
  • An eleven-point curve analysis was conducted for each peptide at the final peptide concentrations tested in each assay (in nM): 10000, 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1. [000123] There was no peptide control used to determine endogenous levels of cGMP.
  • Peptides were incubated for 30 minutes at 37°C. After 30 minutes, the supematants were removed and the cells were lysed with 0.1 M HC1, for 30 mins on ice. After 30 minutes,
  • lysates were pipetted off and placed into a 96-well HPLC plate and spun at 10,000 g for 10 minutes to remove any cell debris. Supematants from the previous spin were removed and placed into a fresh 96-well HPLC plate. Samples were diluted with an equal volume of 1 M ammonium acetate (pH 7) to neutralize samples for better chromatography. A 2x cGMP standard curve was prepared in 0.1 M HC1 and then diluted with an equal volume of 1 M ammonium acetate, with the following final concentrations (in nM): 1024, 512, 256, 128, 64, 32, 16, 8, 4, 2, 1.
  • cGMP concentrations were determined from each sample using the LC/MS conditions (Table 1 below) and the calculated standard curve. EC50 values were calculated from concentration-response curves generated with GraphPad Prism Software.
  • Figure 1 shows the effect on T84 cGMP dose response for Peptide 1 and Peptide 17.
  • Table 2 lists exemplary peptides of the present invention tested, with the summary of the EC50 values for each peptide at pH 5 and pH 8. The ratio of the ECso at pH 8 and pH S for each peptide is also provided.
  • T84 cells were grown in monolayers on T-150 plastic flasks to 60-70% confluency in Dulbecco's Modified Eagle Medium: Ham's F-12 50/50 media (DMEM/F12) + 5% fetal bovine serum (FBS).
  • the cells were harvested by gentle scraping with a cell scraper and cells collected by centrifugation at 2000 g for 10 minutes at 4 °C.
  • the cells were washed twice by resuspending gently in phosphate buffered saline (PBS) and collecting them by centrifugation as above.
  • PBS phosphate buffered saline
  • TFYCCELCCNPACAGCY (SEQ ID NO: 71) (Enterotoxin STp; Bachem H-6248) in 0.5 mL water, which was sent to Perkin-Elmer Life and Analytical Sciences (N. Billerica, MA) for iodination using the lactoperoxidase method recited in Marchanolis, J.J., "An enzymic method for the trace iodination of immunoglobulins and other proteins", Biochem. J. (1969) 113, 299- 305.
  • Perkin-Elmer purified the labeled tracer by HPLC using a Waters C-18 ⁇ column (25 cm) previously equilibrated with 10 mM ammonium acetate pH 5.8.
  • the binding reactions were assembled in duplicate in 0.2 mL containing: 2.5 x 10 s T84 cells (0.25 mg protein), 200,000 cpm [ 125 rj-STp (41 fmol, 200 pM), 0.1 to 3,000 nM competitor, and 0.5% bovine serum albumin (BSA).
  • the binding assays at pH 5.0 were conducted in DMEM 20 mM 2-(N-morpholino) ethanesulfonic acid (MES).
  • the binding assays at pH 8.0 were performed in DMEM/20 mM N-2-Hydroxyethylpiperazine-N'-2-Ethane Sulfonic Acid (HEPES)/50 mM sodium bicarbonate.
  • the control reactions did not contain a competitor (total) or no cells.
  • the buffer solutions were prepared first, and then protease-free BSA was added to 0.5%.
  • the radioligand was added to a final concentration of 0.001 ⁇ Cy ⁇ L.
  • Preparation of competitor peptide stock solutions were made by dissolving peptides to 1 mg/mL in 50 mM sodium phosphate pH 6.0. Concentrations were calculated from the peptide molecular weight provided in the Certificate of Analysis. Competitor dilutions were made in 50 mM sodium phosphate pH 6.0 that contained 20 times the final concentration of peptide to be tested in the binding reaction (20X competitor).
  • the binding reactions were assembled in the following order: i. Radioligand and BSA in buffer solution.
  • the binding reactions were mixed gently and incubated at 37°C for 1 hr. Separation of membrane bound from free radioligand was conducted by applying the binding reactions to 2.5 cm Whatman GF/C glass-fiber filters (pretreated with 1% polyvinylpyrrolidone in PBS) using vacuum filtration. The filters were rinsed twice with 5 mL ice-cold PBS buffer and
  • the purpose of this assay was to test the effect of the guanylate cyclase C peptides on in vivo gastrointestinal transit in mice. Orally-dosed guanylate cyclase C agonists have been demonstrated to increase the % Distance Travelled by a charcoal meal in mice.
  • the assay may be an indicator of the activity of the described guanylate cyclase C peptides to increase upper GI transit in the small intestine of patients.
  • Test peptide and vehicle were administered in 200 uL doses by oral gavage. Seven minutes after dosing the test peptides, 200 pL of the charcoal/gum arabic suspension was dosed by oral gavage. After 15 minutes, mice were sacrificed by C0 2 overdose. The gastrointestinal tract was removed from the esophagus to the caecum. The total length of the small intestine was measured from the pyloric junction to the ileocaecal junction. The distance travelled by the charcoal was measured from the pyloric junction to the charcoal front. The Distance Travelled (%) was determined as (distance travelled by charcoal/total length of the small intestine) x 100. Data were entered into the GraphPad Prism software program and analyzed by ANOVA using a Bonferroni multiple comparison test post-hoc. Plots of data and ED50S were also determined using the GraphPad Prism software package.
  • Table 4 Potency of exemplary peptides in the gastrointestinal transit assay in mice.
  • Example 4 Effect on cGMP levels and secretion in ligated intestinal loops in rodents
  • the loops were injected with 200 ⁇ , of either peptide/GC-C agonist (0.1-5 ug) or vehicle (20 mM Tris, pH 7.5 or Krebs Ringer, lOmM Glucose, HEPES buffer (KRGH)). Following a recovery time of up to 90 minutes the loops were excised. Weights were recorded for each loop before and after removal of the fluid contained therein. The length of each loop was also recorded. A weight to length ratio (W L) for each loop was calculated to determine the effects of the GC-C agonist peptide described herein on secretion. Loop fluid volume was also determined.
  • W L weight to length ratio

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Abstract

La présente invention concerne des peptides, des compositions et des méthodes associées permettant de traiter des troubles et affections du tractus gastro-intestinal supérieur (par exemple la dyspepsie, la gastroparésie, l'iléus gastrique postopératoire, un trouble fonctionnel de l'œsophage, un trouble fonctionnel gastroduodénal, un reflux gastro-œsophagien ou un ulcère du duodénum ou de l'estomac), ainsi que d'autres maladies et affections décrites dans les présentes.
PCT/US2010/059294 2009-12-07 2010-12-07 Traitement des troubles gastro-intestinaux WO2011071927A2 (fr)

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RU2012128509/04A RU2012128509A (ru) 2009-12-07 2010-12-07 Способы лечения заболеваний желудочно-кишечного тракта
US13/514,158 US8735360B2 (en) 2009-12-07 2010-12-07 Treatments for gastrointestinal disorders
CN201080063196.9A CN102822194B (zh) 2009-12-07 2010-12-07 用于胃肠病症的治疗
US14/286,145 US20140256634A1 (en) 2009-12-07 2014-05-23 Treatments for Gastrointestinal Disorders
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WO2012170804A1 (fr) * 2011-06-08 2012-12-13 Ironwood Pharmaceuticals, Inc. Traitements destinés à des troubles gastro-intestinaux
US8735360B2 (en) 2009-12-07 2014-05-27 Ironwood Pharmaceuticals, Inc. Treatments for gastrointestinal disorders
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JP2016514671A (ja) * 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド グアニル酸シクラーゼのアゴニストおよびその使用
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KR101714448B1 (ko) * 2015-07-10 2017-03-09 가톨릭대학교 산학협력단 위 점막 손상의 예방 및 치료용 조성물 및 헬리코박터 파이로리 균의 우레아제 활성 저해능을 지닌 조성물
JP7071284B2 (ja) 2016-05-06 2022-05-18 トリシダ・インコーポレイテッド 酸塩基障害を処置するためのＨＣｌ結合性組成物およびその方法
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US8735360B2 (en) 2009-12-07 2014-05-27 Ironwood Pharmaceuticals, Inc. Treatments for gastrointestinal disorders
WO2012170766A1 (fr) * 2011-06-08 2012-12-13 Ironwood Pharmaceuticals, Inc. Traitements de troubles gastro-intestinaux
WO2012170804A1 (fr) * 2011-06-08 2012-12-13 Ironwood Pharmaceuticals, Inc. Traitements destinés à des troubles gastro-intestinaux
US9527887B2 (en) 2011-06-08 2016-12-27 Ironwood Pharmaceutical, Inc. Treatments for gastrointestinal disorders
US9617305B2 (en) 2011-06-08 2017-04-11 Ironwood Pharmaceuticals, Inc. Treatments for gastrointestinal disorders
JP2014524444A (ja) * 2011-08-17 2014-09-22 アイアンウッド ファーマシューティカルズ インコーポレイテッド 消化器疾患の治療
JP2019085415A (ja) * 2011-08-17 2019-06-06 アイアンウッド ファーマシューティカルズ インコーポレイテッド 消化器疾患の治療
JP2016514671A (ja) * 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド グアニル酸シクラーゼのアゴニストおよびその使用
US10118946B2 (en) 2013-03-15 2018-11-06 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
US10597424B2 (en) 2013-03-15 2020-03-24 Bausch Health Ireland Limited Agonists of guanylate cyclase and their uses

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