WO2007095737A1 - Polythérapie pour le traitement du diabète, comprenant un agoniste d'exendine et un composé de gastrine - Google Patents

Polythérapie pour le traitement du diabète, comprenant un agoniste d'exendine et un composé de gastrine Download PDF

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Publication number
WO2007095737A1
WO2007095737A1 PCT/CA2007/000266 CA2007000266W WO2007095737A1 WO 2007095737 A1 WO2007095737 A1 WO 2007095737A1 CA 2007000266 W CA2007000266 W CA 2007000266W WO 2007095737 A1 WO2007095737 A1 WO 2007095737A1
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WIPO (PCT)
Prior art keywords
gastrin
exendin agonist
compound
gastrin compound
exendin
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PCT/CA2007/000266
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English (en)
Inventor
Antonio Cruz
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Waratah Pharmaceuticals Inc.
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Publication of WO2007095737A1 publication Critical patent/WO2007095737A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/595—Gastrins; Cholecystokinins [CCK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2207—Gastrins; Cholecystokinins [CCK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons

Definitions

  • Exenatide is a 39-amino acid peptide incretin mimetic that exhibits activities similar to the mammalian incretin hormone glucagon-like peptide 1 (GLP-I). Exenatide is used in combination with metformin and/or a sulfonylurea medication to treat Type 2 diabetes. It has been reported that exenatide decreases blood glucose toward target levels and is associated with weight loss. The effects on glucose control are thought to be due to several properties including stimulating the insulin response in response to glucose and preventing glucagon (a hormone which raises blood sugar) release after meals.
  • GLP-I mammalian incretin hormone glucagon-like peptide 1
  • an exendin agonist and a gastrin compound provides beneficial effects in the prevention and/or treatment of conditions and/or diseases for which exendin agonists or gastrin compounds have been demonstrated to have a therapeutic effect, including but not limited to diabetes, hypertension, chronic heart failure, fluid retentive states, obesity, metabolic syndrome and related conditions.
  • Combinations of an exendin agonist and a gastrin compound may be selected to provide unexpectedly additive effects or greater than additive effects i.e. synergistic effects.
  • the invention relates to compositions, conjugates, and methods for the prevention and/or treatment of a condition and/or disease disclosed herein comprising or consisting essentially of a therapeutically effective amount of an exendin agonist and a gastrin compound that provide beneficial effects.
  • a composition, conjugate, or method of the invention may provide sustained beneficial effects following treatment or termination of treatment.
  • Prolonged efficacy may be evidenced in Type 1 and Type 2 diabetes by stimulation of ⁇ -cell regeneration, increases in pancreatic ⁇ cell mass, prolonged increases in C- peptide production, increases in pancreatic insulin production, increases in pancreatic insulin content and insulin release into plasma, and/or about normal blood glucose levels compared with exendin alone.
  • the invention contemplates a composition, preferably a pharmaceutical composition, comprising or consisting essentially of an exendin agonist and a gastrin compound that provide beneficial effects relative to an exendin agonist alone.
  • a pharmaceutical composition comprising an exendin agonist and a gastrin compound that provide beneficial effects, preferably sustained beneficial effects, following treatment.
  • a pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier, excipient, or vehicle.
  • the invention also contemplates a pharmaceutical composition
  • a pharmaceutical composition comprising an exendin agonist and a gastrin compound, both optionally together with pharmaceutically acceptable carriers, excipients, or vehicles in separate containers and intended for simultaneous or sequential administration to provide beneficial effects, preferably sustained beneficial effects.
  • a method for preparing a pharmaceutical composition of an exendin agonist and a gastrin compound adapted to provide beneficial effects, preferably sustained beneficial effects, following treatment, comprising preparing a composition comprising the exendin agonist, a gastrin compound, and a pharmaceutically acceptable carrier, excipient, or vehicle.
  • a method is provided for preparing a stable pharmaceutical composition of an exendin agonist and a gastrin compound adapted to provide beneficial effects, preferably sustained beneficial effects, following treatment, comprising preparing a composition comprising the exendin agonist, a gastrin compound, and a pharmaceutically acceptable carrier, excipient, or vehicle effective to physically stabilize the exendin agonist.
  • the invention further relates to the use of an exendin agonist and a gastrin compound, a composition, or conjugate of the invention for preventing, and/or ameliorating disease severity, disease symptoms, and/or periodicity of recurrence of a condition and/or disease disclosed herein.
  • the invention still further relates to the prevention and/or treatment, in a subject, of diseases and/or conditions disclosed herein using an exendin agonist and a gastrin compound, a composition, or conjugate of the invention.
  • the invention provides a method for the prevention and/or intervention of a condition and/or disease discussed herein in a subject comprising co-administering at least one exendin agonist and at least one gastrin compound to a subject in need thereof.
  • the invention relates to inducing islet neogenesis in a subject comprising contacting pancreatic islet precursor cells with an exendin agonist and a gastrin compound, composition, or conjugate of the invention in a sufficient amount to increase proliferation of pancreatic islet precursor cells in the subject thereby inducing islet neogenesis.
  • the invention provides in some aspects methods for the potentiation of a gastrin compound in the treatment of a condition and/or disease in a subject, in particular diabetes and related diseases, disorders, or conditions, comprising co-administering with the gastrin compound at least one exendin agonist to the subject.
  • the invention provides a method for the prevention and/or intervention of a condition and/or disease disclosed herein in a subject comprising co-administering at least one exendin agonist and at least one gastrin compound to a subject in need thereof.
  • the invention provides methods for treating cells using an exendin agonist and gastrin compound of the invention, or compositions, or conjugates of the invention.
  • the invention relates to a method for expanding and differentiating stem cells, progenitor cells or islet precursor cells into islet cells in particular insulin secreting cells, enhancing proliferation of insulin secreting cells, and/or sustaining islet cells in particular insulin secreting cells or islet precursor cells.
  • Cells may be contacted with an exendin agonist and a gastrin compound in culture or in a subject.
  • a method for treating a condition and/or disease disclosed herein comprising administering an exendin agonist and a gastrin compound, a composition or conjugate of the invention, with a plurality of cells to a subject in need thereof to thereby produce beneficial effects, preferably sustained beneficial effects.
  • the compounds, composition or conjugate are administered systemically.
  • pancreatic islet cells that have been exposed in culture to a sufficient amount of a gastrin compound and an exendin agonist, or a composition or conjugate of the invention, to increase the number of pancreatic beta cells in the islets in the patient; optionally the population of pancreatic islet cells can be grown in culture for a time sufficient to expand a population of pancreatic beta cells prior to transplantation.
  • the invention also contemplates the use of a composition comprising a combination of at least one exendin agonist and at least one gastrin compound for the preparation of one or more medicament for preventing and/or treating a condition and/or disease.
  • the invention further contemplates use of an exendin agonist in combination with a gastrin compound for the manufacture of a medicament for the treatment of a condition and/or disease.
  • Still further the invention provides use of an exendin agonist for the manufacture of a medicament for the treatment of a condition and/or disease to be used in combination with a gastrin compound.
  • the invention relates to the use of synergistically effective amounts of at least one exendin agonist and at least one gastrin compound for the preparation of a medicament for preventing or treating a condition and/or disease disclosed herein.
  • the invention relates to the use of an exendin agonist and a gastrin compound for the preparation of a medicament which has a protracted profile of action relative to an exendin agonist alone.
  • the invention additionally provides uses of a pharmaceutical composition and a conjugate of the invention in the preparation of medicaments for the prevention and/or treatment of conditions and/or diseases disclosed herein.
  • the medicaments provide beneficial effects, preferably sustained beneficial effects following treatment.
  • Medicaments may comprise an exendin compound and a gastrin compound in separate containers and intended for simultaneous or sequential administration, in particular to provide beneficial effects, preferably sustained beneficial effects.
  • the present invention relates to a method of prevention and/or treatment comprising a combination of active agents which may be administered separately or as conjugates
  • the invention also provides a kit comprising an exendin agonist and a gastrin compound, separately or together, and a pharmaceutical composition or conjugate of the invention in kit form.
  • Figure 1 are graphs showing blood glucose levels (mMol/1) in NOD mice treated with vehicle, gastrin
  • Figure 2 are graphs showing blood glucose levels (mMol/1) in NOD mice treated with vehicle, gastrin (10 ⁇ g/kg), gastrin (30 ⁇ g/kg), exenatide (3 ⁇ g/kg), exenatide (3 ⁇ g/kg) + gastrin (10 ⁇ g/kg), and exenatide (3 ⁇ g/kg) + gastrin (30 ⁇ g/kg).
  • Figure 3 is a bar graph showing blood glucose levels (mMol/1) in NOD before therapy, NOD diabetic, NOD normoglycemic, and NOD-scid, treated with vehicle, gastrin (10 ⁇ g/kg), gastrin (30 ⁇ g/kg), exenatide (3 ⁇ g/kg), exenatide (3 ⁇ g/kg) + gastrin (10 ⁇ g/kg), and exenatide (3 ⁇ g/kg) + gastrin (30 ⁇ g/kg).
  • Figure 4 is a bar graph showing HbAIc (%) in NOD before therapy, NOD diabetic, NOD normoglycemic, and NOD-scid, treated with vehicle, gastrin (10 ⁇ g/kg), gastrin (30 ⁇ g/kg), exenatide (3 ⁇ g/kg), exenatide (3 ⁇ g/kg) + gastrin (10 ⁇ g/kg), and exenatide (3 ⁇ g/kg) + gastrin (30 ⁇ g/kg).
  • Figure 5 is a bar graph showing pancreatic insulin levels ( ⁇ g) in NOD before therapy, NOD diabetic, NOD normoglycemic, and NOD-scid, treated with vehicle, gastrin (10 ⁇ g/kg), gastrin (30 ⁇ g/kg), exenatide (3 ⁇ g/kg), exenatide (3 ⁇ g/kg) + gastrin (10 ⁇ g/kg), and exenatide (3 ⁇ g/kg) + gastrin (30 ⁇ g/kg).
  • Figure 6 is bar graph showing plasma C-peptide levels (pmmol/ml) in NOD before therapy, NOD diabetic, NOD normoglycemic, and NOD-scid, treated with vehicle, gastrin (10 ⁇ g/kg), gastrin (30 ⁇ g/kg), exenatide (3 ⁇ g/kg), exenatide (3 ⁇ g/kg) + gastrin (10 ⁇ g/kg), and exenatide (3 ⁇ g/kg) + gastrin (30 ⁇ g/kg).
  • Figure 7 is a graph showing the correlation of blood glucose levels (mmol/1) and pancreatic insulin content ( ⁇ g) in NOD mice treated with exenatide and gastrin.
  • Figure 8 is a bar graph showing fasting blood glucose levels (mM) in NOD mice treated with vehicle,
  • Figure 10 shows histological examinations, in particular total ⁇ -cell mass, in NOD mice before treatment and after treatment with gastrin (3 ⁇ g/kg/day) + GLP- 1(300 ⁇ g/kg/day).
  • the terms “comprising,” “including,” and “such as” are used in their open and non- limiting sense.
  • the recitation of numerical ranges by endpoints herein includes all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about.”
  • the term “about” means plus or minus 0.1 to 50%, 5-50%, or 10-40%, preferably 10-20%, more preferably 10% or 15%, of the number to which reference is being made.
  • composition or method comprising "a gastrin compound” includes a mixture of two or more gastrin compounds and a composition or method comprising "an exendin agonist” includes a mixture of two or more exendin agonists.
  • Selected compounds described herein may contain one or more asymmetric centers and may give rise to enantiomers, diasteriomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-. Therefore, the invention includes all such possible diasteriomers and enantiomers as well as their racemic and optically pure forms.
  • Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and A geometric isomers. All tautomeric forms are intended to be included within the scope of the invention.
  • administering and “administration” refer to the process by which a therapeutically effective amount of compounds or a composition or conjugate contemplated herein is delivered to a subject for prevention and/or treatment purposes.
  • Compositions are administered in accordance with good medical practices taking into account the subject's clinical condition, the site and method of administration, dosage, patient age, sex, body weight, and other factors known to physicians.
  • a carrier, excipient, or vehicle refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered.
  • a carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular composition.
  • a carrier, excipient, or vehicle is selected to stabilize an exendin agonist and/or gastrin compound.
  • the compounds disclosed herein also include "pharmaceutically acceptable salt(s)".
  • pharmaceutically acceptable salts are meant those salts which are suitable for use in contact with the tissues of a subject or patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art and are described for example, in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66:1.
  • Pharmaceutically acceptable salt(s) include acidic or basic groups which may be present in the compounds disclosed herein.
  • Acids which are used to prepare pharmaceutically acceptable acid addition salts of compounds disclosed herein are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, para-toluenesulfonate and pamoate [i.e., l,l'-methylene- bis-(2-hydroxy-3-naphthoate)] salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride,
  • Suitable non-toxic base salts include, without limitation, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N- methylglucamine (meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • alkali metal cations e.g., potassium and sodium
  • alkaline earth metal cations e.g., calcium and magnesium
  • ammonium or water-soluble amine addition salts such as N- methylglucamine (meglumine)
  • meglumine N- methylglucamine
  • the terms also refer to preventing the recurrence of a condition and/or disease or of one or more symptoms associated with such condition and/or disease.
  • An objective of prevention, treatment, or intervention is to combat the condition and/or disease and includes administration of the active compounds to prevent or delay the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating or partially eliminating the condition and/or disease.
  • a “beneficial effect” refers to an effect of a combination of an exendin agonist and a gastrin compound, or composition or conjugate thereof that is greater than the effect of either of the compounds alone.
  • the beneficial effect includes favourable pharmacological effects, therapeutic effects, and/or improved pharmacokinetic properties and/or biological activity.
  • a beneficial effect may be an additive effect or synergistic effect.
  • beneficial effects include but are not limited to the following: reduced or absent islet inflammation, stimulation of ⁇ -cell regeneration, effective ⁇ - cell replacement, normalizing hyperglycemia, preventing, slowing or reducing development of hyperglycemia, increased pancreatic ⁇ -cell mass, increasing ⁇ -cell mass in pancreatic ducts, increased pancreatic insulin content, increased release of insulin into plasma, decreased disease progression, increased survival, or elimination or partial elimination of a condition and/or disease.
  • the beneficial effect is a "sustained beneficial effect" where the beneficial effect is sustained for a prolonged period of time after termination of treatment.
  • one or more of the aforementioned effects are sustained for a prolonged period of time after termination of treatment.
  • a beneficial effect may be sustained for at least about 1, 2, 4, 6, 8, 10, 1 to 4 weeks, 2 to 4 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 12 weeks, 2 to 24 weeks, 2 weeks to 12 months, and 2 weeks to 18 months following treatment.
  • the period of time a beneficial effect is sustained may correlate with the duration and timing of the treatment.
  • a subject may be treated continuously for about 2 to 8 weeks, 2 to 12 weeks, 2 to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, or periodically.
  • a sustained beneficial effect may manifest as one or more of stimulation of ⁇ -cell regeneration, increased C-peptide production, increased pancreatic insulin production, increased pancreatic insulin content, increased pancreatic ⁇ -cell mass, increased release of insulin into plasma, and/or, about normal or low blood glucose levels for a prolonged period following treatment.
  • the beneficial effect may be a statistically significant effect in terms of statistical analysis of an effect of the two compounds versus the effects of each of the compounds. "Statistically significant” or “significantly different” effects or levels with two compounds compared with each compound alone may represent levels that are higher or lower than a standard. In embodiments of the invention, the difference may be 1.5, 2, 3, 4, 5, or 6 times higher or lower compared with the effect obtained with each compound alone.
  • An "additive effect" of an exendin agonist and a gastrin compound refers to an effect that is equal to the sum of the effects of the two individual compounds
  • a “synergistic effect" of an exendin agonist and a gastrin compound refers to an effect that is greater than the additive effect which results from the sum of the effects of the two individual compounds.
  • Combination treatment “Combination treatment”, “combination therapy”, and “administering in combination” are used interchangeably herein and mean that the active ingredients are administered concurrently to a patient being treated.
  • each component may be administered at the same time, or sequentially in any order at different points in time. Therefore, each component may be administered separately, but sufficiently close in time to provide the desired effect, in particular a beneficial, additive, or synergistic effect.
  • the first compound may be administered in a regimen which additionally comprises treatment with the second compound.
  • the term refers to administration of an exendin agonist and a gastrin compound to a patient within one week, two weeks, three weeks, one, two three, four, five or six months, or one year, including separate administration of two medicaments each containing one of the compounds as well as simultaneous administration whether or not the two compounds are combined in one formulation or whether they are two separate formulations.
  • a “medicament” refers to a pharmaceutical composition suitable for administration of a pharmaceutically active compound(s) (e.g. an exendin agonist and/or a gastrin compound) to a patient.
  • “Therapeutically effective amount” relates to the amount or dose of active compounds (e.g.
  • exendin agonist and gastrin compound compositions or conjugates of the invention that will lead to one or more desired beneficial effects, preferably one or more sustained beneficial effects.
  • a "therapeutically effective amount” can provide a dosage which is sufficient in order for prevention and/or treatment of a subject to be effective compared with no treatment.
  • a therapeutically effective amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance to elicit a desired response in the individual.
  • a dosage regimen may be adjusted to provide the optimum therapeutic response (e.g. one or more beneficial effect, in particular a sustained beneficial effect). For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • “Synergistically effective amount” relates to the amount of dose of active compounds (e.g. exendin agonist and gastrin compound), compositions or conjugates of the invention that will provide a synergistic effect, in particular a synergistic beneficial effect.
  • active compounds e.g. exendin agonist and gastrin compound
  • Suboptimal dose or suboptimal dosage refers to a dose or dosage of an active compound which is less than the optimal dose or dosage for that compound when used in mono-therapy.
  • Sequence identity of two amino acid sequences, or of two nucleic acid sequences is defined as the percentage of amino acid residues or nucleotides in a candidate sequence that are identical with the amino acid residues in a polypeptide or nucleic acid sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining amino acid or nucleic acid sequence identity can be achieved in various conventional ways, for instance, using publicly available computer software including the GCG program package (Devereux J. et al, Nucleic Acids Research 12(1): 387, 1984); BLASTP, BLASTN, and FASTA (Atschul, S.F.
  • an “analog” refers to a polypeptide wherein one or more amino acid residues of a parent or wild-type polypeptide have been substituted by another amino acid residue, one or more amino acid residues of a parent or wild-type polypeptide have been inverted, one or more amino acid residues of the parent or wild-type polypeptide have been deleted, and/or one or more amino acid residues have been added to the parent or wild- type polypeptide.
  • Such an addition, substitution, deletion, and/or inversion may be at either of the N-terminal or C-terminal end or within the parent or wild-type polypeptide, or a combination thereof.
  • Mutations may be introduced into a polypeptide by standard methods, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative substitutions can be made at one or more predicted non-essential amino acid residues.
  • a "conservative amino acid substitution” is one in which an amino acid residue is replaced with an amino acid residue with a similar side chain.
  • Amino acids with similar side chains are known in the art and include amino acids with basic side chains (e.g. Lys, Arg, His), acidic side chains (e.g. Asp, GIu), uncharged polar side chains (e.g. GIy, Asp, GIu, Ser, Thr, Tyr and Cys), nonpolar side chains (e.g.
  • Mutations can also be introduced randomly along part or all of the native sequence, for example, by saturation mutagenesis. Following mutagenesis the variant polypeptide can be recombinantly expressed.
  • exendin agonist includes naturally occurring exendin peptides that are found in the salivary secretions of the Gila-monster and the Mexican Bearded Lizard, reptiles that are endogenous to Arizona and Northern Mexico.
  • Exendin-3 [SEQ. ID. NO. 10) is present in the salivary secretions of Heloderma horridum (Mexican Beaded Lizard), and exendin-4 (SEQ. ID. NO. 1 1) is present in the salivary secretions of He loderm suspectum (GiIa monster) (Eng, J., et al., J. Biol. Chem., 265:20259-62, 1990; Eng, J., et al., J. Biol.
  • stable exendin analogue or derivative means an exendin analogue or a derivative which exhibits an in vivo plasma elimination half-life of at least 10 hours in a subject as determined by the method described below.
  • an exendin agonist has the empirical formula C 184 H 282 N 50 O 60 S and a molecular weight of 41.86.6 daltons, and the following amino acid sequence: H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser- Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-NH 2 [SEQ. ID NO. 14].
  • exendin-4 (1-30) [SEQ. ID NO 4: His GIy GIu GIy Thr Phe Thr Ser Asp Leu Ser Lys GIn Met GIu GIu GIu Ala VaI Arg Leu Phe He GIu Trp Leu Lys Asn GIy GIy]; exendin-4 (1-30) amide [SEQ. ID NO 5: His GIy GIu GIy Thr Phe Thr Ser Asp Leu Ser Lys GIn Met GIu GIu GIu Ala VaI Arg Leu Phe He GIu Trp Leu Lys Asn GIy GIy-NH 2 ]; exendin-4 (1-28) amide [SEQ.
  • the exendin-4 analogue is HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPS SGAPPSKKKKKK [SEQ. ID NO. 3].
  • a "gastrin/CCK receptor” refers to a member of the G-protein-coupled receptor family that displays a characteristic binding affinity for a cholecystokinin (CCK) including without limitation CCK-8, desulfated CCK- 8, CCK-33, CCK-4, or gastrins including without limitation desulfated or sulfated gastrin-17, or pentagastrin, or other CCK or gastrin analogues or family members.
  • CCK cholecystokinin
  • a gastrin compound may be selected that is a gastrin/CCK receptor ligand including but not limited to cholecystokinin (CCK) such as CCK 58, CCK 33, CCK 22, CCK 12 and CCK 8, or a cholecystokinin agonist, and the like.
  • a gastrin compound may also include substances that increase the secretion of endogenous gastrins, cholecystokinins or similarly active peptides from sites of tissue storage. Examples of these are gastrin agonists, and soya bean trypsin inhibitor which increases CCK stimulation.
  • gastrin 17 (little gastrin) [SEQ. ID NO. 17 or 18]
  • gastrin 14 [SEQ. ID NO. 21]
  • gastrin 8 gastrin 6 [SEQ. ID NO.
  • a modified gastrin preferably comprises TrpMetAspPhe-NH 2
  • a modified gastrin comprises at least amino acids 1-34, 18-34 or 29-34 of
  • SEQ. ID NO. 15 or 16 or amino acids 1-17, 2-17, 12-17, or 14-17 of SEQ. ID NO. 17 or 18.
  • a gastrin compound used in aspects of the methods, compositions, and conjugates of the invention may comprise gastrin 17 and analogs and derivatives thereof.
  • the gastrin compound is synthetic human gastrin 1 having 17 amino acid residues with a Leu residue at amino acid position 15 [SEQ. ID NO. 18].
  • a gastrin compound used in the methods, compositions and conjugates of the invention may comprise gastrin 34 and analogs and derivatives thereof.
  • the gastrin compound is a synthetic human gastrin 34 with methionine or leucine at position 32 [SEQ ID NO. 15 or 16].
  • Modified gastrin compounds for use in the present invention comprise the modified gastrin compounds described in PCT/CA03/01778 and US Application Serial No. 10/728,082 incorporated in their entirety by reference.
  • a modified gastrin can be a gastrin derivative or analogue comprising a minimal sequence of 6 amino acids (from the C-terminal end) of a gastrin, in particular amino acid residues 1 to 34, 18 to 34 or 29-
  • a reactive group capable of undergoing an addition reaction.
  • reactive groups include without limitation thiols, alpha amino groups, epsilon amino groups, carboxyl groups or aromatic rings.
  • a reactive group is generally capable of linking a gastrin sequence, directly or indirectly via a crosslinking agent and/or spacer region, to a carrier.
  • a reactive group may be introduced by adding or substituting an amino acid comprising a reactive group, for example by adding a cysteine or lysine. Therefore, a modified gastrin may comprise a gastrin sequence (e.g. gastrin-34 or gastrin 17) wherein at least one reactive amino acid (e.g. cysteine or lysine) is added or substituted.
  • a reactive amino acid can be at a terminal region, in particular an N-terminal region.
  • a modified gastrin may also optionally comprise a spacer.
  • a spacer can interact with a reactive group, for example, an amino acid comprising a reactive group.
  • a spacer can be one or more amino acids, peptides, peptidomimetics, or small organic molecules.
  • a spacer can comprise at least one amino acid, preferably at least two, three, four or five amino acids and in certain embodiments it is a sequence of several amino acids, including without limitation alanine or glycine.
  • a spacer can comprise alternating amino acids (e.g. glycine and/or alanine), non-alternating amino acids, a random sequence or a particular sequence.
  • a spacer can be synthesized as part of, or may be chemically attached to an amino acid of a gastrin sequence.
  • a modified gastrin may optionally comprise a cross-linking agent.
  • a cross-linking agent may comprise a homobifunctional or heterobifunctional portion for interaction directly or indirectly with a gastrin, spacer and/or a reactive group.
  • a cross-linking agent may interact with a gastrin sequence or a spacer, or it may be added to a reactive group at the end (in particular N-terminus) of a modified gastrin.
  • a cross-linking agent can be any agent that can link a gastrin sequence and a carrier directly or via a spacer.
  • homobifunctional crosslinking agents include without limitation amino group directed homobifunctional cross-linking reagents such as bisimidates (e.g. methyl acetimidate-HCl), bifunctional aryl halides (e.g. l,5-dichloro-2,4-dinitrobenzene), bifunctional acylating agents (e.g. diisocyanates), bifunctional sulfonyl halides (e.g. phenol-2,4-disulfonyl-chloride), bifunctional acylazides (e.g.
  • heterobifunctional crosslinkers include amino and sulfhydryl group directed bifunctional reagents (e.g. N-succinimidyl-3-(2-pyridyldithio propionate, carboxyl and either sulfhydryl or amino group directed bifunctional reagents (e.g. p-nitrophenyl diazoacetate), and carbonyl and sulfhydryl group directed bifunctional reagents (e.g. l-(aminooxy)-4-[3-nitro-2- pyridyl)dithio)]butane).
  • amino and sulfhydryl group directed bifunctional reagents e.g. N-succinimidyl-3-(2-pyridyldithio propionate, carboxyl and either sulfhydryl or amino group directed bifunctional reagents (e.g. p-nitrophenyl diazoacetate), and carbonyl and sulfhydry
  • a modified gastrin can optionally comprise a carrier which may be a polymer.
  • a carrier may be a polymer of amino acids (proteins), sugars (polysaccharides), nucleosides, synthetic polymers and mixtures thereof.
  • a protein carrier may be a protein found in the circulatory system. Examples of protein carriers found in the circulatory system, in particular the human circulatory system, include without limitation plasma components such as serum, purified serum proteins such as albumin (in particular human serum albumin), transferrin, or an immunoglobulin, red blood cell proteins such as glycophorin A and AE-I , sugar binding proteins such as a lectin, inactivated enzymes, phosphate and sulphate binding proteins, and lipid binding proteins.
  • Carriers may be attached to a gastrin or spacer by way of reactive groups on, or introduced to, the carrier, gastrin, and/or spacer.
  • carriers can be covalently attached to reactive groups (such as thiol groups, alpha and epsilon amino groups, carboxyl groups or aromatic groups) on a gastrin or spacer which may be present or added by chemical modification of the gastrin or spacer.
  • a modified gastrin can comprise a gastrin of SEQ ID NOS 15, 16, 17, or 18 and a carrier.
  • a group of modified gastrin compounds include compounds having an amino acid sequence comprising from the amino terminus Z-Y 111 -X n -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 , wherein AAi is Tyr or Phe, AA 2 is GIy, Ala, or Ser, AA 3 is Tip, VaI, or He, AA 4 is Met or Leu, AA 5 is Asp or GIu, and AA 6 is Phe or Tyr and wherein AA 6 is optionally amidated;
  • Z is a carrier, in particular a polymer and when the polymer is a protein Z is an amino acid sequence;
  • Z is a protein, in particular a protein of the circulatory system, more particularly a serum protein, still more particularly albumin, most particularly human serum albumin.
  • X is one or more amino acid residues from position 18 to position 28 of SEQ ID NO: 15. Therefore, the gastrin compounds by virtue of the presence of X, can have any of the gastrin sequences from positions 18-28, 19-28, 20-28, 21-28, etc.
  • the gastrin compound optionally contains an amino acid spacer (Y) of length m, and m is 0 to about 20 residues.
  • X is one or more amino acid residues from position 1 to 11 or 2 to 1 1 of SEQ ID NO: 17 or 18. Therefore, the gastrin compounds by virtue of the presence of X, can have any of the gastrin sequences from positions 2 to 1 1 , 3 to 1 1 , 4 to 1 1 , 5 to 1 1, etc.
  • the gastrin compound optionally contains an amino acid spacer (Y) of length m, and m is 0 to about 20 residues.
  • a gastrin compound includes a modified gastrin of the formula X n -AA 1 -AA 2 - AA 3 - AA 4 -AA 5 -AA 6 where there is no spacer (Y) and m is 0, which may further comprise a bifunctional cross-linking agent for interaction or linkage to a carrier Z, where Z further comprises a non-proteinaceous polymer such as dextran or PEG.
  • a modified gastrin compound particularly described herein may further comprise an amino terminal cysteine or lysine residue.
  • the gastrin component contains at least amino acid residues 29-34 of SEQ ID NO: 15 or 16, and it is associated with a polymer, a lipid or a carbohydrate.
  • the polymer may be a synthetic or naturally occurring polymer.
  • the term polymer includes a protein polymer of amino acids, and is not limited to a synthetic polymer.
  • the polymer may be a polyethylene glycol (PEG) or a dextran.
  • a modified gastrin compound can be based on SEQ ID NO: 15 or 2 or "big" gastrin- 34 and have a residue at position 32 which is a methionine or a leucine, respectively.
  • Another particular modified gastrin compound comprises a structure C-Y m -X, wherein C is Cys or Lys, Y m is an optional spacer region comprising m amino acid residues of a small neutral amino acid, and X is at least six amino acid residues comprising at least positions 12-17 of gastrin-17 (SEQ ID NO: 17 or 18) or at least positions 29-34 of gastrin-34 (SEQ ID NO: 15 or 16).
  • This modified gastrin compound can further comprise a bifunctional cross-linking agent wherein one reactive portion of the cross-linking agent is covalently linked to C, and the other reactive portion is covalently linked to a polymer or protein.
  • AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 in a modified gastrin compound is Tyr-Gly-Trp-Met-Asp-Phe [SEQ ID NO. 24] or Tyr-Gly-Trp-Leu-Asp-Phe [SEQ ID NO. 25].
  • a gastrin compound used in the methods, compositions and conjugates of the invention is gastrin 34 or gastrin 17 or portions thereof, directly or indirectly interacting or associated with a serum protein, in particular albumin or an immunoglobulin, more particularly human serum albumin.
  • a gastrin compound comprises synthetic human gastrin 34 having 2-34 amino acid residues of SEQ ID NO. 15 or 16, and optionally an N-terminal cysteine and/or a carrier; synthetic human gastrin having 1-17 amino acid residues with a Leu residue at amino acid position 15 [SEQ ID NO. 18] and optionally an N-terminal cysteine residue; and a synthetic human gastrin having amino acid residues 2 to 17 or 5-17 of SEQ ID NO. 17 or 18, optionally with an N-terminal cysteine residue and/or a carrier (e.g. PEG or human serum albumin) linked via a spacer [e.g.
  • a carrier e.g. PEG or human serum albumin
  • Gly-Ala-Gly-Ala-Gly-Ala-Gly-Ala-Gly-Ala-Gly-Ala-Gly-Ala i.e. (GA) 5 ] [SEQ ID NO. 26], in particular, a synthetic human gastrin having amino acid residues 2 to 17 or 5-17 of SEQ ID NO. 17 or 18, with a human serum albumin (HSA) polymer linked via a GIy- Ala-Gly-Ala-Gly-Ala-Gly-Ala-Gly-Ala-Gly- Ala [ ie. (GA) 5 ] spacer, and optionally an N-terminal cysteine residue.
  • HSA human serum albumin
  • the gastrin compound is a leucine substituted gastrin 17 of SEQ ID NO. 18.
  • a gastrin compound may also be characterized by the following properties: isoelectric point of about 3.4; purity of at least about 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and/or a molecular mass of about 2080.2 ⁇ 2 Da.
  • Gastrin compounds may be synthesized by chemical synthesis using techniques well known in the chemistry of proteins such as solid phase synthesis (Merrif ⁇ eld, 1964, J. Am. Chem. Assoc. 85:2149-2154) or synthesis in homogenous solution (Houbenweyl, 1987, Methods of Organic Chemistry, ed. E. Wansch, Vol. 15 I and II, Thieme, Stuttgart). The synthesis may be performed using manual procedures or by automation. Automated synthesis may be carried out, for example, using an Applied Biosystems 43 IA peptide synthesizer (Perkin Elmer). Gastrin compounds may also be obtained from commercial sources. For example, synthetic human gastrin 17 with methionine or leucine at position 15 are available from Bachem AG, Bubendorf, (Switzerland) and from Research Plus Inc (New Jersey, USA).
  • a “gastrin agonist” refers to any substance that fully or partially mimics a reaction, activity, or function of a gastrin or initiates such reaction, activity, or function, or reduces or prevents inhibition of any reaction, activity or function of a gastrin.
  • a gastrin agonist can include substances that increase the secretion of endogenous gastrins, cholecystokinins or similarly active peptides from sites of tissue storage.
  • a gastrin agonist is a gastrin secretagogue.
  • a gastrin agonist is selected that provides, in combination with an exendin agonist beneficial effects in a subject (e.g., a diabetic subject).
  • a gastrin agonist is selected that provides an about 1.5 to 1000 fold, 5 to 1000 fold, 10 to 1000 fold, 10 to 500 fold, 10 to 100 fold, 5 to 100, 10 to 50, 5 to 50, 10 to 25, 1.5 to 10, 1.5 to 5, 1.5 to 3, 1.5 to 5, 1.5 to 10, 1.5 to 20, 1.5 to 25, 3 to 5, 3 to 10, 3 to 15, 3 to 25, 5 to 15, or 5 to 20 fold increase in plasma gastrin.
  • the term includes analogs, derivatives, fragments and modifications of a wild-type gastrin agonist and chimeric polypeptides comprising a gastrin agonist.
  • a gastrin agonist is a proton pump inhibitor or a histamine-2 receptor antagonist.
  • a "proton pump inhibitor” and "PPI" are used interchangeably herein and include a substance which inhibits gastric acid secretion by blocking the proton pump and/or increasing gastrin secretion.
  • the term "proton pump inhibitor” refers to any acid labile pharmaceutical agent possessing pharmacological activity as an inhibitor of H + /K + -ATPase. More particularly it contemplates substances which covalently bind to H+/K+-ATPase, the enzyme responsible for gastric acid secretion.
  • PPIs Fellenius et al., Substituted Benzimidazoles Inhibit Gastric Acid Secretion by Blocking H + , K + -ATPase, Nature, 290:159-161 (1981); Wallmark et al, The Relationship Between Gastric Acid Secretion and Gastric H + , K + -ATPase Activity, J.
  • a proton pump inhibitor may be selected for use in the compositions, conjugates, methods and uses disclosed herein based on one or more of the following properties: (i) a bioavailability greater than about 40%, 41%, 42%, 43%, 44%, 45%, 50%, 50% to 55%, 60%, 65%, 70%, 75%, 66%, 77%, 78%, 79%, 80%, 80% to 85%, 90%, 95%, 100%, 65-100%, or 80-95%; (ii) a plasma elimination half life greater than about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, or 3 hours, and (iii) it does not bind to cysteine 892 of the alpha subunit of the proton pump.
  • omeprazole, its salts, polymorphs, and any of its analogs and derivatives thereof are not encompassed within the term "proton pump inhibitor”.
  • a PPI includes compounds comprising a 2-[(2-pyridinyl) methylsulphinyl]- 1 H-benzimidazole skeleton or a related skeleton, which may optionally be substituted in various forms.
  • a proton pump inhibitor may, if desired, be in the form of free base, free acid, salt, ester, solvates (in particular hydrates), anhydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or the like, provided that the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or any other pharmacologically suitable derivative is therapeutically active.
  • PPIs may be mentioned in the context of the present invention: 2-[2-(N-isobutyl-N- methylamino)benzyl-sulphinyl]benzimidazole (INN: leminoprazole) (DE-A-3531487); 2-(4-methoxy-6,7,8,9- tetrahydro-5H-cyclohepta[b]pyridin-9-ylsulphinyl)-l H-benzimidazole (INN: nepaprazole) (EP-A-O 434 999); 2- (4-methoxy-3-methyl-pyridin-2-ylmethylsulphinyl)5-pyrrol-l-y-lH-benzimidazole (IY-81 149), 5-methoxy-2- [(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-l-H-inidazo[4,5-b]pyridine(tenatoprazole),
  • proton pump inhibitors include but are not limited to: soraprazan (Altana); ilaprazole (U.S. Pat. No. 5,703,097) (II- Yang); AZD-0865 (AstraZeneca); dontoprazole; dontoprazole; donprazole; perprazole; ransoprazole; pariprazole; YH-1885 (PCT Publication WO 96/05177) (SB-641257) (2-pyrimidinamine, 4-(3,4-dihydro-l- methyl-2(lH)-isoquinolinyl)-N-(4-fluorophenyl)-5,6-dimethyl-, monohydrochloride) (YuHan); phenylalkyl- amino derivatives of condensed carbapenem cpds (WO-A-9523149); BY-1 12 (Altana); SPI-447 (Imidazo(l,2- a)thieno
  • the proton pump inhibitor is selected from the group consisting of 2-[3-methyl-4-
  • the proton pump inhibitor is selected from the group consisting of 5-methoxy-2-[(4- methoxy-3,5-dimethyl-2-pyridinyl)-methylsulphinyl]-lH-benzimidazole (omeprazole), 5-methoxy-2-[(S)-[(4- methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulphinyl]-lH-benzimidazole(esomeprazole), 2-[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl) methylsulphinyl]- lH-benzimidizole(lansoprazole), 2- ⁇ [4-(3-methoxypropoxy)-3- methylpyridin-2-yl]methylsulphinyl ⁇ -lH-benzimidazole(rabeprazole), 5-difluoromethoxy- 2-[(3,4-di-methoxy-methoxy-
  • a proton pump inhibitor is in the form of a salt.
  • a salt of a proton pump inhibitor may be prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, ftimaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, ⁇ -hydroxybutyric, galactaric and galacturonic acids.
  • acid addition salts are prepared from the free base of a proton pump inhibitor using conventional methods involving reaction of the free base with a suitable acid.
  • suitable acids for preparing acid addition salts include without limitation organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • an acid addition salt is converted to a free base by treatment with a suitable base.
  • an acid addition salt is a halide salt, which is prepared using hydrochloric or hydrobromic acids.
  • the basic salt is an alkali metal salt, such as a sodium salt or copper salt.
  • salts of proton pump inhibitors include without limitation: a sodium salt form such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or a magnesium salt form such as esomeprazole magnesium or omeprazole magnesium described in U.S. Pat. No. 5,900,424; a calcium salt form; or a potassium salt form such as the potassium salt of esomeprazole described in U.S. Pat. No. 6,511,996.
  • Other salts of esomeprazole are described in U.S. Pat. Nos. 4,738,974 and 6,369,085. Salt forms of pantoprazole and lansoprazole are disclosed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.
  • esters of proton pump inhibitors are utilized.
  • An ester may be prepared by functionalization of hydroxyl and/or carboxyl groups which may be present within the molecular structure of the drug.
  • the esters are acyl-substituted derivatives of free alcohol groups, such as moieties derived from carboxylic acids of the formula -RCOOR 1 where R 1 is an alkyl group in particular a lower alkyl group.
  • R 1 is an alkyl group in particular a lower alkyl group.
  • An ester can be converted to a free acid, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
  • a proton pump inhibitor or its salts can be in a crystalline form. Crystals of a proton pump inhibitor may contain variable amounts of solvent.
  • the term "proton pump inhibitor” includes all solvates, in particular all hydrates, of the proton pump inhibitors and their salts.
  • the proton pump inhibitor is a salt or hydrate including without limitation pantoprazole-sodium sesquihydrate [pantoprazole-sodium ⁇ l .5 H 2 O], (-)-pantoprazole-sodium sesquihydrate, pantoprazole-magnesium dihydrate, omeprazole-magnesium, omeprazole-magnesium tetrahydrate, esomeprazole-magnesium and esomeprazole- magnesium tetrahydrate
  • the proton pump inhibitor is a substituted bicyclic aryl-imidazole, wherein the aryl group may be, for example, a pyridine, a phenyl, or a pyrimidine group which is attached to the 4- and 5-positions of the imidazole ring.
  • Proton pump inhibitors comprising a substituted bicyclic aryl-imidazole include, but are not limited to, omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontop
  • Substituted bicyclic aryl-imidazole compounds as well as their salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivatives may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry. See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry, (1992); Howarth et al.; Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).
  • a tautomer of a substituted bicyclic aryl-imidazole includes without limitation tautomers of omeprazole such as those disclosed in U.S. Pat. Nos. 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; and 6,444,689; and U.S. Publication No. 02/0156103.
  • An example of an isomer of a substituted bicyclic aryl-imidazole is an isomer of omeprazole including but not limited to an isomer disclosed in: Oishi et al., Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. patent publication No. 02/0156284; and
  • An amide of a bicyclic aryl-imidazole compound may be prepared using techniques known to those skilled in the art or described in the pertinent literature.
  • an amide may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with an amine group e.g., ammonia or a lower alkyl amine.
  • Suitable polymorphs include but are not limited to the polymorphs described in PCT Publication No. WO 92/08716, and U.S. Pat. Nos. 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579;
  • a proton pump inhibitor suitable for use in the invention is a benzimidazole compound, for example, a benzimidazole compound described in the following patent documents U.S. Pat. Nos.
  • a proton pump inhibitor comprises or is selected from the group consisting of omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontopraz
  • a proton pump inhibitor comprises or is selected from the group consisting of tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, Vietnameseprazole, periprazole, ransoprazole, pariprazole, leminoprazole; or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof.
  • a "histamine-2 receptor antagonist” or “H-2 antagonist” refers to a compound which blocks H-2 receptors, but does not have meaningful activity in blocking histamine- 1 receptors. Selective H-2 antagonists include compounds which are disclosed in US Pat. Nos. 5,294,433, 5,364,616, and US Patent Application No.
  • 20050042283 including without limitation cimetidine [Merck Index, 11th edition (1989), p. 354 (entry no. 2279) and Physicians' Desk Reference, 46th edition (1992), p. 2228]; etintidine (U.S. Pat. No. 4,112,234); ranitidine or its hydrochloride salt (AH-19065) [U.S. Pat. No. 4,128,658, Merck Index, 1 lth edition (1989), p. 1291 (entry no.
  • sufotidine U.S. Pat. No. 4,670,448
  • ebrotidine U.S. Pat. No. 4,728,755
  • HE-30-256 U.S. Pat. No. 4,738,960
  • D-16637 U.S. Pat. No. 4,738,983
  • FRG-8813 U.S. Pat. Nos. 4,912,101 and 4,977,267)
  • FRG-8701 U.S. Pat. No. 4,837,316
  • impromidine U.K. Patent Specification No. 1,531,237)
  • L-643728 European Patent Application No. 0,040,696)
  • MK-208 U.S. Pat. No. 4,283,408
  • HB-408 European Patent Application No. 0,186,275
  • burimamide and metiamide.
  • Condition(s) and/or disease(s) refers to one or more pathological symptoms or syndromes for which either or both of an exendin agonist or a gastrin compound provide a beneficial or therapeutic effect.
  • the condition and/or disease may require reduction of blood glucose levels, inhibition of gastric acid secretion, increased pancreatic insulin content, increased pancreatic ⁇ -cell mass, inhibition of apoptosis of ⁇ -cells, stimulation of proliferation or differentiation of ⁇ -cells, and reduction of body weight.
  • conditions and/or diseases include but are not limited to dyslipidemia, hyperglycemia, severe hypoglycemic episodes, stroke, left ventricular hypertrophy, arrhythmia, bacteraemia, septicaemia, irritable bowel syndrome, functional dyspepsia, diabetes, catabolic changes after surgery, stress induced hyperglycemia, respiratory distress syndrome, gastric ulcers, myocardial infarction, impaired glucose tolerance, hypertension, chronic heart failure, fluid retentive states, metabolic syndrome and related diseases and disorders, obesity, diabetic complications as well as symptoms of other diseases in which tissue is damaged due to elevated glucose levels, including Alzheimer's Disease, Parkinson's Disease, and other age-related, tissue-degenerative diseases, as well as the artherogenic effects of elevated leptin, for example in patients with impaired glucose tolerance and obese non- diabetic patients.
  • diabetes as used herein means any manifested symptoms of diabetes in any mammal including experimental animal models, and including human forms such as Type 1 and Type 2 diabetes, early stage diabetes, and a pre-diabetic condition characterized by mildly decreased insulin or mildly elevated blood glucose levels.
  • Diabetes disease processes may be derived from multiple causative factors and are characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Increased and premature morbidity and mortality are associated with persistent or uncontrolled hyperglycemia.
  • Abnormal glucose homeostasis may be associated both directly and indirectly with alterations of lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic diseases.
  • Type 2 diabetes mellitus Conditions and/or diseases associated with diabetes, particularly Type 2 diabetes mellitus, include but are not limited to diabetic nephropathy, diabetic retinopathy and diabetic neuropathy, macular degeneration, coronary heart disease, myocardial infarction, diabetic cardiomyopathy, myocardial cell death, coronary artery diseases, peripheral arterial disease, stroke, limb ischemia, vascular restenosis, foot ulcerations, endothelial dysfunction and/or atherosclerosis.
  • patients with Type 2 diabetes mellitus may be at an increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy.
  • pre-diabetic condition describes a subject demonstrating a symptom in terms of insulin or glucose level, and/or demonstrating a susceptibility to diabetes or a related condition due to family history, genetic predisposition, or obesity in the case of Type 2 diabetes, and includes a subject who has previously had diabetes or a related condition and is subject to risk of recurrence.
  • a condition and/or disease may be selected from the group consisting of (a) Type 1 or Type 2 diabetes mellitus and related diseases, disorders or conditions (including but not limited to diabetic nephropathy, diabetic retinopathy and diabetic neuropathy); (b) insulin resistance and syndrome X, obesity and related diseases, disorders or conditions (including but not limited to Insulin Resistance, Type 2 Diabetes Mellitus, Reproductive Disorders, Cardiovascular Disease, Pulmonary Disease, Gallstones and Fasting- induced cholecystitis, Cancers and Cutaneous Disease), Cushing's Syndrome, Hypothyroidism, Insulinoma, Craniopharyngioma and Other Disorders Involving the Hypothalamus; (c) congestive heart failure, left ventricular hypertrophy, survival post myocardial infarction (Ml), coronary artery diseases, atherosclerosis, angina pectoris, thrombosis, (d) hypertension including hypertension in the elderly, familial dyslipidemichypertension
  • the condition and/or disease is diabetes, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis, inflammatory bowel disease, Colitis Ulcerosa, Morbus Crohn, and/or metabolic syndrome or B-cell protection, preferably an exendin agonist and a gastrin compound are used as therapeutic active substances for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance.
  • ITT impaired glucose tolerance
  • an exendin agonist and a gastrin compound are used as therapeutic active substances for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance.
  • Insulinotropic activity refers to an ability of a substance to stimulate insulin secretion in response to elevated glucose levels to produce or increase glucose uptake by cells and decreased serum glucose or blood glucose levels. Methods known in the art can be employed to assay for insulinotropic activity. For example, in vitro and in vivo methods may be used that measure insulin and/or C-peptide levels. Compounds, compositions or conjugates described herein have insulinotropic activity if islet cells secrete insulin in the presence of the compounds, compositions, or conjugates above background levels or levels in the absence of the compounds, compositions, or conjugates. A compound may be administered to an animal and the insulin concentration can be monitored over time.
  • Islet neogenesis means formation of new beta cells by differentiation, which may or may not have the characteristics of stem cells, which have the ability to reproduce in an unlimited manner.
  • the invention is related to compositions, conjugates, and methods that utilize an exendin agonist and a gastrin compound to provide beneficial effects.
  • the invention relates to compositions, conjugates, and methods for the prevention, intervention and/or treatment of a condition and/or disease disclosed herein comprising an exendin agonist and a gastrin compound.
  • compositions, conjugates and methods of the invention provide enhanced beneficial effects, in particular sustained beneficial effects relative to an exendin agonist and/or a gastrin compound alone.
  • the beneficial effects may be additive or synergistic effects, preferably synergistic effects.
  • beneficial effects in particular sustained beneficial effects of a composition, combination treatment, or conjugate of the invention may manifest as one or more of the following: a) An increase in pancreatic insulin levels relative to the levels measured in the absence of an exendin agonist and a gastrin compound or for each compound alone after administration to a subject with symptoms of diabetes.
  • the compounds together induce at least about a 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% increase in pancreatic insulin levels in a subject.
  • the combination of an exendin agonist and a gastrin compound stimulate pancreatic insulin levels that approximate 65 to 95%, 70-95%, 75 to 90%, 80-90% or 90-100% of normal levels.
  • the compounds together induce at least about a 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% increase in pancreatic insulin content and release into plasma, c) A reduction of an absence of symptoms of islet inflammation after administration to a subject with symptoms of diabetes. d) A decrease in blood glucose levels relative to the levels measured in the absence of the compounds or for each compound alone in subjects with symptoms of diabetes.
  • the compounds induce at least about a 1%, 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in blood glucose levels.
  • the compounds yield blood glucose levels about or close to the levels common in a normal subject.
  • the compounds together induce at least about a 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45%, or 50% increase in C-peptide levels,
  • a reduction in destruction of beta-cells Preferably the compounds induce at least about a 1%,
  • the compounds induce at least about a 1%, 2%,
  • the compounds induce at least about a 1%, 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% increase in ⁇ -cell mass.
  • k) A reduction, prevention, or slowing of the rate of disease progression in a subject with diabetes. 1) A reduction or prevention of the development of ketoacidosis in patients with symptoms of diabetes.
  • m) A reduction or decrease in insulin delivery or usage compared with the absence of the compounds or for each compound alone in diabetic subjects.
  • the compounds provide at least about a 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, 100%, 30-100%, 30-80%, or 35-75%, reduction in insulin delivery or usage, n) A reduction or prevention of the development of severe hyperglycemia. o) An increase in survival in a subject with symptoms of diabetes.
  • beneficial effects or sustained beneficial effects comprise or consist essentially of two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or thirteen of a) through m).
  • beneficial effects or sustained beneficial effects comprise or consist essentially of a), b), and c); a), b), c), and d); a), b), c), d), and e); a), b), c), d), e), and f); a), b), c), d), e), f), and g); a), b), c), d), e), f), g), and h); a), b), c), d), e), 0, g), h), and i); a), b), c), d), e), f), g), h), i) and j); a), d), and e); a), d), and e); a), d), e), and h); a), d), e), and h); a), d), e), and h); a), d), e), and h); a), d), e
  • One or more of these beneficial effects or sustained beneficial effects can be demonstrated in a diabetic subject or disease model, for example a non-obese (NOD) mouse with symptoms of diabetes, using standard methods known to the skilled artisan.
  • NOD non-obese
  • commercially available methods and kits may be used to assay pancreatic insulin levels, glucose levels, C-peptide levels and hemoglobin AIc.
  • a gastrin compound may be selected for particular embodiments in the present invention and to provide a specific beneficial effect(s) based on characteristics including its insulinotrophic activity, the ability to augment the activity of an exendin agonist (in particular to enhance the insulinotropic effects of an exendin agonist), and/or increase the physical or chemical stability of an exendin agonist.
  • a gastrin compound can also be selected based on its ability to stimulate proliferation/differentiation of beta cells, and its in vivo half-life.
  • a gastrin compound used in the methods, compositions, and conjugates of the invention is gastrin 17 and analogs and derivatives thereof.
  • the gastrin compound is synthetic human gastrin I having 17 amino acid residues with a Leu residue at amino acid position 15 [SEQ ID NO. 18].
  • a gastrin compound used in the methods, compositions and conjugates of the invention is gastrin 34 and analogs and derivatives thereof.
  • the gastrin compound is a synthetic human gastrin 34 with methionine or leucine at position 32 [SEQ ID NO. 15 or 16].
  • a gastrin compound comprises synthetic human gastrin 34 having
  • (GA) 5 ] [SEQ ID NO. 26], in particular, a synthetic human gastrin having amino acid residues 2 to 17 or 5-17 of SEQ ID NO. 17 or 18, optionally with a human serum albumin (HSA) polymer linked via a G Iy- AIa-G Iy- Ala-Gly- AIa- Gly-Ala-Gly-Ala [ ie. (GA) 5 ] spacer, and optionally an N-terminal cysteine residue.
  • HSA human serum albumin
  • the gastrin compound is a leucine substituted gastrin 17 of SEQ ID NO. 18.
  • a gastrin compound may also be characterized by the following properties: isoelectric point of about 3.4; purity of at least about 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and/or a molecular mass of about 2080.2 ⁇ 2 Da.
  • An exendin agonist may be selected for particular applications in the present invention based on one or more of the following characteristics: ability to initiate a signal transduction pathway resulting in insulinotropic activity; insulinotropic activity; stimulation of beta cell proliferation/differentiation; resistance to DP IV cleavage; and, an in vivo half-life of at least about 15 minutes to 24 hours, preferably 2 to 10 hours or 2 to 8 hours in humans using conventional methods (see for example, the method described in US 2003/0144206).
  • the exendin agonist is a stable exendin agonist in particular a stable exendin analogue or derivative, or a stable exendin-4 or exendin-3 analogue or derivative.
  • the exendin agonist is exenatide, in particular injectable exenatide, most preferably Byetta®.
  • the exendin is a long-acting release formulation of exenatide.
  • compositions of the invention can be selected that provide beneficial effects, in particular statistically significant beneficial effects or sustained beneficial effects, compared with an exendin agonist or a gastrin compound alone.
  • beneficial effects in respect to a diabetic condition may be evidenced by one or more of the beneficial effects described herein, in particular one, two, three, four, five, six, seven, eight, nine or ten of the beneficial effects described above in a) through o).
  • the invention provides a pharmaceutical composition with beneficial effects, in particular statistically significant beneficial effects or sustained beneficial effects comprising exendin-4 and gastrin- 17(leu) [SEQ ID NO. 18].
  • the invention provides a pharmaceutical composition with beneficial effects, in particular statistically significant beneficial effects or sustained beneficial effects comprising exenatide and gastrin- 17(leu) [SEQ ID NO. 18].
  • the invention also provides a pharmaceutical composition with beneficial effects, in particular statistically significant beneficial effects or sustained beneficial effects, comprising an exendin agonist selected from the group consisting of exendin-3, exendin-4 or analogues or derivatives thereof, in particular H-His-Gly- Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-T ⁇ -Leu-Lys-
  • an exendin agonist selected from the group consisting of exendin-3, exendin-4 or analogues or derivatives thereof, in particular H-His-Gly- Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-T ⁇ -Leu-Lys-
  • Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 and a gastrin compound having an amino acid sequence comprising, from the amino terminus, Z-Y 1n -X n -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 , wherein AA, is Tyr or Phe, AA 2 is GIy, Ala, or Ser, AA 3 is Trp, VaI, or He, AA 4 is Met or Leu, AA 5 is Asp or GIu, and AA 6 is Phe or Tyr; Z is a polymer and when the polymer is a protein Z is an amino acid sequence; Y n , is an optional spacer region comprising m amino acid residues of a small neutral amino acid including but not limited to serine and alanine, and X is any consecutive portion of residues 1-28 of SEQ ID NO: 15 or 16, or residues 1-11 of SEQ ID NO.
  • compositions which has been adapted for administration to a subject to provide sustained beneficial effects to treat a condition and/or disease, preferably diabetes.
  • the composition is in a form such that administration to a subject results in blood glucose levels that are about normal that persist for a prolonged period of time after cessation of treatment, increased pancreatic insulin content and release into plasma, increased pancreatic ⁇ -cell mass, stimulation of ⁇ -cell regeneration, and/or increased C-peptide production.
  • This invention provides a conjugate comprising an exendin agonist linked to or interacting with a gastrin compound wherein the interaction is for example, via an amino or a carboxyl group.
  • the invention also relates to isolated covalent conjugates of the invention, and compositions comprising covalent conjugates of the invention.
  • An exendin agonist may be conjugated to a species via an ester bond between an OH and a COOH of a gastrin compound.
  • Conjugates of an exendin agonist and a gastrin compound may be conjugated with an intermediate spacer or linker.
  • a suitable spacer or linker may be a mono- or disaccharide, an amino acid, a sulfate, a succinate, an acetate, or an oligomeric polymeric spacer or linker comprising one or more of such moieties.
  • the invention also provides methods of preparing conjugates that result in conjugates with improved pharmacokinetic properties, biological activity, and/or beneficial effects.
  • the methods comprise incubating the exendin agonist with a gastrin compound under conditions that allow formation of a covalent linkage between the two compounds.
  • the invention therefore contemplates a process for preparing a covalent conjugate comprising an exendin agonist covalently bonded or linked to a gastrin compound, the process comprising: incubating the exendin agonist with a gastrin compound under conditions and at a pH and for a time sufficient for formation of a covalent bond or linkage between the exendin agonist and gastrin compound; and isolating the covalent conjugate.
  • the above process for preparing a conjugate comprising an exendin agonist and a gastrin compound may provide a conjugate with a substantial amount of an exendin agonist covalently linked to the exendin agonist.
  • N-terminal or C-terminal fusion proteins or chimeric proteins comprising an exendin agonist conjugated with a gastrin compound, optionally with a spacer or linker, may also be prepared by fusing, through recombinant techniques, the N-terminal or C-terminal sequence of an exendin agonist and the sequence of a gastrin compound.
  • the invention relates to a conjugate prepared by a process described herein.
  • the invention also relates to pharmaceutical formulation or composition comprising conjugates of the invention and a pharmaceutically acceptable carrier, excipient, or vehicle.
  • the invention further relates to a pharmaceutical formulation or composition of substantially pure covalent conjugates comprising an exendin agonist covalently linked to a gastrin compound which provides beneficial effects preferably sustained beneficial effects compared to the exendin agonist alone.
  • a pharmaceutical formulation is provided consisting essentially of covalent conjugates comprising an exendin agonist covalently linked without an intermediate spacer or linker to a gastrin compound.
  • a pharmaceutical formulation is provided consisting essentially of covalent conjugates comprising an exendin agonist covalently linked with an intermediate spacer or linker to a gastrin compound.
  • composition or conjugate comprising an exendin agonist and a gastrin compound having greater sustained insulinotropic activity following treatment compared with the activity of an exendin agonist alone.
  • the invention provides methods for the prevention, treatment and/or intervention of a condition and/or disease in a subject comprising administering a gastrin compound and an exendin agonist or a pharmaceutical composition of the invention to provide a beneficial effect, in particular a sustained beneficial effect.
  • exendin-4 agonist and gastrin- 17(Ieu) [SEQ ID NO. 18] are administered.
  • exenatide and gastrin- 17(leu) [SEQ ID NO. 18] are administered.
  • an exendin agonist is an exendin-4, in particular, H- His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2, , and a gastrin compound comprises an amino acid sequence comprising, from the amino terminus, Z-Y m -X n -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 , wherein AA 1 is Tyr or Phe, AA 2 is GIy, Ala, or Ser, AA 3 is Trp, VaI, or He, AA 4 is Met or Le
  • AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 is Tyr-Gly-Trp-Met-Asp-Phe or Tyr-Gly-Trp-Leu- Asp-Phe.
  • Z is a serum protein, in particular human serum albumin.
  • the invention provides a method for the prevention and/or intervention of a condition and/or disease discussed herein in a subject comprising administration of at least one exendin agonist and at least one gastrin compound.
  • An exendin agonist and a gastrin compound may be directly administered to a subject or contacted with cells (e.g. stem cells or progenitor cells) and administered to a subject.
  • the invention also provides a combination treatment for preventing and/or treating a condition and/or disease discussed herein in a subject comprising administering to the subject a therapeutically effective amount of at least one exendin agonist and a gastrin compound which provides beneficial effects following treatment.
  • the invention provides a combination treatment or intervention which provides sustained beneficial effects following treatment.
  • the invention also relates to a method of treatment comprising administering a therapeutically effective amount of at least one exendin agonist in combination with the administration of at least one gastrin compound which upon administration to a subject with symptoms of diabetes produces beneficial effects, preferably sustained beneficial effects, manifested as about normal blood glucose levels, reduced insulin use, increased ⁇ -cell mass, and/or increased pancreatic insulin.
  • therapeutically effective amounts of an exendin agonist and a gastrin compound are combined prior to administration to a subject.
  • therapeutically effective amounts of an exendin agonist and a gastrin compound are mixed at a physiologically acceptable pH.
  • the invention provides a method for stimulating beta cell proliferation in a subject comprising administering a therapeutically effective amount of a composition or conjugate of the invention, or administering in combination an exendin agonist and a gastrin compound.
  • the invention provides a method for increasing the number and/or size of beta cells in a subject comprising administering a therapeutically effective amount of a composition or conjugate of the invention or administering in combination an exendin agonist and a gastrin compound.
  • the invention provides a method for preventing or treating Type 1 or Type 2 diabetes comprising administering a therapeutically effective amount of a composition or conjugate of the invention, or administering in combination an exendin agonist and a gastrin compound.
  • the invention provides a method for ameliorating progression of disease or obtaining a less severe stage of disease in a person suffering from Type 1 diabetes comprising administering a therapeutically effective amount of a composition or conjugate of the invention, or administering in combination an exendin agonist and a gastrin compound.
  • the invention provides a method for ameliorating progression of disease or obtaining a less severe stage of disease in a person suffering from Type 2 diabetes comprising administering a therapeutically effective amount of a composition or conjugate of the invention, or administering in combination an exendin agonist and a gastrin compound.
  • the invention further relates to inducing islet neogenesis in a subject comprising contacting islet precursor cells with an exendin agonist and a gastrin compound, composition, or conjugate of the invention in a sufficient amount to increase proliferation of islet precursor cells in the subject thereby inducing islet neogenesis
  • the invention contemplates a method of expanding a functional beta cell mass of pancreatic islet transplants in a diabetic patient, the method comprising administering to the patient a therapeutically effective amount of an exendin agonist and a gastrin compound, or a composition or conjugate of the invention
  • the invention also relates to a method for enhancing proliferation of insulin secreting cells in culture comprising contacting the cells with an exendin agonist and a gastrin compound, composition or conjugate of the invention in sufficient amounts to enhance proliferation of the cells.
  • the amount of proliferation may be significantly different compared with that achieved in the absence of the compounds, composition or conjugate.
  • the amount of proliferation is significantly greater compared with an exendin agonist or a gastrin compound alone
  • the invention further relates to a method for sustaining islet cells or precursor cells in culture comprising culturing the cells in the presence of an exendin agonist and a gastrin compound, composition, or conjugate of the invention in an amount sufficient to sustain the cells in culture.
  • a method for treating a subject with a condition and/or disease described herein comprises contacting ex vivo a plurality of cells with an exendin agonist and a gastrin compound, or a composition or conjugate of the invention of the invention, optionally culturing the cells, and administering the cells to the subject in need thereof.
  • the cells are pancreatic ductal cells and the amount of compounds, composition, or conjugate used in the method is generally effective to increase the amount of insulin secreting cells in the subject.
  • the cells may be autologous (i.e. from the same subject), or may be from another individual of the same species, or from a different species.
  • Modes of administration of cells include without limitation systemic intracardiac, intracoronary, intravenous, intradermal, or intra-arterial injection and injection directly into the tissue or organ at the intended site of activity, or in proximity to the site of activity.
  • a cell preparation can be administered by any convenient route, for example by infusion or bolus injection and can be administered together with other biologically active agents. Administration in some aspects is preferably systemic.
  • Methods of the invention may further comprise measuring or monitoring one or more of the following markers: blood glucose, serum glucose, blood glycosylated haemoglobin, pancreatic beta cell mass, serum insulin, pancreatic insulin levels, morphometrically determined beta cell mass, amount of insulin secreting cells, and glucose responsiveness of insulin secreting cells.
  • the invention additionally provides uses of a pharmaceutical composition and a conjugate of the invention in the preparation of medicaments for beneficial effects, preferably sustained beneficial effects, in the treatment of conditions and/or diseases.
  • Therapeutic efficacy and toxicity of compounds, compositions and conjugates of the invention may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals such as by calculating a statistical parameter such as the ED 50 (the dose that is therapeutically effective in 50% of the population) or LD 50 (the dose lethal to 50% of the population) statistics.
  • the therapeutic index is the dose ratio of therapeutic to toxic effects and it can be expressed as the ED 50 ZLD 50 ratio.
  • Pharmaceutical compositions which exhibit large therapeutic indices are preferred.
  • the compounds, compositions, medicaments, and conjugates of the present invention can be administered by any means that produce contact of the active agent(s) with the agent's sites of action in the body of a subject or patient.
  • the active ingredients can be administered simultaneously or sequentially, and in any order at different points in time, to provide the desired beneficial effects.
  • the compounds, conjugates and compositions can be formulated for sustained release, for delivery locally or systemically. It lies within the capability of a skilled physician or veterinarian to select a form and route of administration that optimizes the effects of the compositions, conjugates, and treatments of the present invention.
  • parenteral administration is generally understood to refer to the injection of a dosage form into the body by a sterile syringe or some other mechanical device such as an infusion pump.
  • parenteral routes include intravenous, intramuscular, subcutaneous, and intraperitoneal routes of administration.
  • the compounds, compositions or conjugates described herein may be combined with distilled water at an appropriate pH.
  • the present invention includes combination treatments providing additive or synergistic activity, or that deliver an additive or synergistically effective amount, or an amount to provide a therapeutically effective amount of an exendin agonist and a gastrin compound, or a conjugate or composition of the invention. Therefore, pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in a synergistically effective amount or a therapeutically effective amount.
  • a pharmaceutical composition or method comprising a therapeutically effective suboptimal dosage of an exendin agonist and a gastrin compound that are more effective at decreasing or reducing glucose levels, increasing ⁇ -cell mass, stimulating ⁇ -cell regeneration, increasing C-peptide, and/or increasing pancreatic insulin production for a sustained period following treatment compared with a dosage of either a gastrin compound or exendin agonist alone.
  • an improved pharmaceutical composition or method comprising therapeutically effective suboptimal amounts of an exendin agonist and a gastrin compound in a form for chronic or acute therapy of a condition and/or disease, in particular diabetes.
  • the compounds or a composition or formulation of the invention may be administered to a subject continuously for 2 weeks to 12 months, 2 weeks to 6 months, 2-16 weeks, 2 weeks to 12 weeks, and/or 2-8 weeks, or periodically.
  • An exendin agonist and a gastrin compound may be in a ratio selected to augment the activity of one or both compounds to produce beneficial effects, in particular a sustained beneficial effect, and/or to produce an additive or synergistic effect.
  • the ratio of an exendin agonist to a gastrin compound may be from 1:1 to 1:200, 1:1 to 1:110, 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1:10, 1:1 to 1:5, and 1:1, in particular 1 : 100.
  • the ratio of a gastrin compound to an exendin agonist may be from 1 : 1 to 1:110, 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1:10, and 1:1 to 1:5.
  • the ratio of an exendin agonist to a gastrin compound is from 1:50 to 1:150, more particularly 1:100.
  • compositions of the present invention typically comprise suitable pharmaceutical diluents, excipients, vehicles, or carriers selected based on the intended form of administration, and consistent with conventional pharmaceutical practices.
  • the carriers, vehicles etc. may be adapted to provide additive, synergistically effective or therapeutically effective amounts of the active compounds.
  • Suitable pharmaceutical diluents, excipients, vehicles, and carriers are described in the standard text, Remington: The Science and Practice of Pharmacy, 21 st Edition. University of the Sciences in Philadelphia (Editor).
  • the active components can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium, sulfate, dicalcium phosphate, mannitol, sorbital, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium, sulfate, dicalcium phosphate, mannitol, sorbital, and the like.
  • the drug components may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Suitable binders e.g. gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums, and waxes
  • lubricants e.g.
  • a pharmaceutical composition has a pH from about 7 to 10.
  • Formulations for parenteral administration of a composition of the invention may include aqueous solutions, syrups, aqueous or oil suspensions and emulsions with edible oil such as cottonseed oil, coconut oil or peanut oil.
  • Dispersing or suspending agents that can be used for aqueous suspensions include synthetic or natural gums, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, and polyvinylpyrrolidone.
  • Compositions for parenteral administration may include sterile aqueous or non-aqueous solvents, such as water, isotonic saline, isotonic glucose solution, buffer solution, or other solvents conveniently used for parenteral administration of therapeutically active agents.
  • a composition intended for parenteral administration may also include conventional additives such as stabilizers, buffers, or preservatives, e.g. antioxidants such as methylhydroxybenzoate or similar additives.
  • a solid form pharmaceutical composition comprising a crystalline or amorphous exendin agonist and a crystalline or amorphous gastrin compound.
  • the invention in another embodiment, relates to a liquid drug formulation comprising pharmaceutically acceptable salts of an exendin agonist and a gastrin compound, and to lyophilized drug formulations that can be reconstituted to provide suspensions that are stable and suitable for parenteral administration.
  • compositions can also be formulated as a depot preparation.
  • long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the fractions may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil), or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions of the invention and components thereof may comprise soluble polymers as targetable drug carriers.
  • compositions After pharmaceutical compositions have been prepared, they can be placed in an appropriate container and labelled for treatment of an indicated condition.
  • labelling would include amount, frequency, and method of administration.
  • the present invention relates to a method of treatment comprising a combination of active agents which may be administered separately or as conjugates
  • the invention also provides a kit comprising an exendin agonist and a gastrin compound, a pharmaceutical composition or conjugate in kit form.
  • the invention also relates to a pharmaceutical kit comprising one bottle with an exendin agonist and another bottle with a gastrin bottle in one box.
  • a kit may comprise a package which houses a container which contains a conjugate or composition of the invention and also houses instructions for administering the conjugate or composition to a subject.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention to provide a beneficial effect, in particular a sustained beneficial effect.
  • Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the labeling, manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • the invention relates to a "kit-of-parts", for example, the components to be combined according to the present invention can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. simultaneously or at different time points.
  • the parts of the kit can then be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit. Time intervals can be selected such that the effect on the condition and/or disease in the combined use of the parts is larger than the effect that would be obtained by use of any one of the components.
  • the invention provides a kit of parts comprising: (a) an amount of an exendin agonist or a pharmaceutically acceptable salt thereof in a first unit dosage; and (b) an amount of a gastrin compound or a pharmaceutically acceptable salt thereof in a second unit dosage, in the form of one or two separate units of the components (a) and (b).
  • the invention further relates to a commercial package comprising at least one exendin agonist and at least one gastrin compound, together with instructions for simultaneous, separate or sequential use.
  • a commercial package comprising as active ingredients at least one exendin agonist and at least one gastrin compound is provided in the form of two or more separate units of the components, together with instructions for its simultaneous, separate or sequential use, or any combination thereof, in the delay of progression or treatment of a condition and/or disease disclosed herein.
  • the present invention also includes compositions, kits and methods of using the compositions and kits of the invention in combination with one or more additional therapeutic agents including without limitation immunosuppressive agents, antidiabetic agents including without limitation insulin sensitivity enhancers, glucose lowering agents, insulin secretagogues, insulin, antiobesity agents, appetite regulating drugs, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with a condition and/or disease, in particular diabetes and obesity, anti-nausea, anti-headache medications, and general medications that treat or prevent side effects.
  • additional therapeutic agents including without limitation immunosuppressive agents, antidiabetic agents including without limitation insulin sensitivity enhancers, glucose lowering agents, insulin secretagogues, insulin, antiobesity agents, appetite regulating drugs, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with a condition and/or disease, in particular diabetes and obesity, anti-nausea, anti-headache medications, and general medications that treat or prevent
  • the additional therapeutic agent is nateglinide, repaglinide, metformin, rosiglitazone, pioglitazone, troglitazone, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, a peroxisome proliferator-activated receptor ⁇ compound, or a pharmaceutically acceptable salt of such a compound.
  • mice I.P. in 0.2 ml, twice daily (8 a.m. and 6 p.m.) for 3 weeks.
  • the mice were monitored daily for urine glucose and weekly for body weight and FBG levels.
  • FBG levels were measured at 8 a.m., 12 hours after food had been withdrawn and 14 hours after the last treatment injection. All treatments were stopped at 3 weeks and the mice continued to be monitored daily for glucosuria and weekly for body weight and FBG levels.
  • Figures 1 to 7 show that a combination therapy of exenatide and gastrin corrects hyperglycemia in NOD mice.
  • Figure 5 shows that a combination therapy with exenatide and gastrin restores pancreatic insulin content in NOD mice.
  • Figure 6 shows that a combination therapy with exenatide and gastrin prevents loss of insulin secretion (plasma C-peptide) after diabetes onset in NOD mice.
  • Figure 7 shows that blood glucose levels in NOD mice treated with exenatide ⁇ gastrin are inversely correlated with pancreatic insulin content.
  • Byetta ® will be administered subcutaneously twice daily for 7 days as per the Byetta ® Product Monograph at 10 ⁇ g per dose.
  • Gl will be administered subcutaneously once daily for 7 days.
  • the starting Gl dose will be 1 mg followed by planned doses of 2 mg and 4 mg.
  • PK Endpoints Plasma concentrations of Gl and Byetta ® (AUC, C max , t max , ti /2 , K e
  • the Treatment Phase is 3 months in duration. Dose levels of Gl will be established in the study described in Example 4. Patients who complete the treatment phase will be followed for 3 months.
  • Byetta ® will be administered subcutaneously twice daily for the duration of the trial (Baseline, Treatment and Follow-up) days as per the Byetta ® Product Monograph. Gl will be administered subcutaneously once daily during the 3 -month Treatment Phase only.
  • Group 1 Vehicle control
  • Group 2 Low dose Gl (1 mg dose)
  • Group 3 High dose G 1 (2 mg dose)
  • PK Endpoints Plasma concentrations of Gl and Byetta ® (AUC, C max , t n , ax , X 112 , K el )
  • the treatment phase is 3 months in duration. Dose levels of Gl will be established in the study described in Example 4. Patients who complete the treatment phase will be followed for 3 months.
  • Byetta ® will be administered subcutaneously twice daily for the duration of the trial (Baseline, Treatment and Follow-up) days as per the Byetta ® Product Monograph. Gl will be administered subcutaneously once daily during the 3-month Treatment Phase only.
  • Group 1 Vehicle control
  • PK Endpoints Plasma concentrations of Gl and Byetta ® (AUC, C max , t max , Ua, K e i)

Abstract

L'invention concerne des compositions, des conjugués, ainsi que des méthodes de prévention et/ou de traitement d'un état et/ou d'une maladie, faisant appel à une quantité thérapeutiquement efficace d'un agoniste d'exendine et d'un composé de gastrine. La combinaison d'un agoniste d'exendine et d'un composé de gastrine permet d'obtenir des effets bénéfiques, en particulier des effets bénéfiques prolongés, dans la prévention et/ou le traitement d'états et/ou de maladies pour lesquels un agoniste d'exendine ou un composé de gastrine ont révélé un effet thérapeutique, comprenant, non limitativement, le diabète, l'hypertension, l'insuffisance cardiaque chronique, les états de rétention hydrique, l'obésité, le syndrome métabolique ainsi que des maladies et troubles associés. Des combinaisons d'un agoniste d'exendine et d'un composé de gastrine peuvent être sélectionnées pour obtenir de manière inattendue des effets additifs ou des effets synergiques
PCT/CA2007/000266 2006-02-21 2007-02-21 Polythérapie pour le traitement du diabète, comprenant un agoniste d'exendine et un composé de gastrine WO2007095737A1 (fr)

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WO2008106779A1 (fr) * 2007-03-02 2008-09-12 Waratah Pharmaceuticals Inc. Composé de gastrine pour le traitement du diabète
US7476388B2 (en) 2001-01-12 2009-01-13 Waratah Pharmaceuticals, Inc. Composition comprising a gastrin/CCK receptor ligand and an EGF receptor ligand
WO2009039994A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009039995A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Big gastrine-i en tant qu'agent thérapeutique
US7560425B2 (en) 2002-06-07 2009-07-14 Waratah Pharmaceuticals Inc. Pharmaceutical composition consisting of rapamycine and gastrin 17(LEU15) and a method for treating diabetes
US7803766B2 (en) 2002-11-21 2010-09-28 Warath Pharmaceuticals, Inc Gastrin compositions and formulations, and methods of use and preparation
WO2011134471A1 (fr) * 2010-04-27 2011-11-03 Zealand Pharma A/S Conjugués peptidiques d'antagonistes du récepteur de glp-1 et de gastrine, et leur utilisation
WO2013064669A1 (fr) * 2011-11-03 2013-05-10 Zealand Pharma A/S Conjugués de peptide agoniste du récepteur du glp-1 et de gastrine
WO2013098408A1 (fr) * 2011-12-30 2013-07-04 Zealand Pharma A/S Conjugués peptidiques agonistes des récepteurs de la cck et du glucagon
US9975939B2 (en) 2012-09-17 2018-05-22 Zealand Pharma A/S Glucagon analogues
US10093713B2 (en) 2013-11-06 2018-10-09 Zealand Pharma A/S GIP-GLP-1 dual agonist compounds and methods
US10131702B2 (en) 2013-11-06 2018-11-20 Zealand Pharma A/S Glucagon-GLP-1-GIP triple agonist compounds
US10253078B2 (en) 2014-10-29 2019-04-09 Zealand Pharma A/S GIP agonist compounds and methods
US10336802B2 (en) 2015-04-16 2019-07-02 Zealand Pharma A/S Acylated glucagon analogue
US10457714B2 (en) 2013-10-17 2019-10-29 Zealand Pharma A/S Acylated glucagon analogues
US10905745B2 (en) 2016-12-09 2021-02-02 Zealand Pharma A/S Acylated GLP-1/GLP-2 dual agonists
CN112759640A (zh) * 2020-12-09 2021-05-07 江苏师范大学 一类glp-1/胃泌素受体双重激动剂及其应用
US11034747B2 (en) 2013-10-17 2021-06-15 Zealand Pharma A/S Glucagon analogues and methods of use
US11795204B2 (en) 2012-07-23 2023-10-24 Zealand Pharma A/S Glucagon analogues

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WO2004037195A2 (fr) * 2002-10-22 2004-05-06 Waratah Pharmaceuticals, Inc. Traitement du diabete
WO2005072045A2 (fr) * 2004-01-30 2005-08-11 Waratah Pharmaceuticals, Inc. Utilisation d'un agoniste de glp-1 associe a des composes gastriniques

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WO2005072045A2 (fr) * 2004-01-30 2005-08-11 Waratah Pharmaceuticals, Inc. Utilisation d'un agoniste de glp-1 associe a des composes gastriniques

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US7476388B2 (en) 2001-01-12 2009-01-13 Waratah Pharmaceuticals, Inc. Composition comprising a gastrin/CCK receptor ligand and an EGF receptor ligand
US7560425B2 (en) 2002-06-07 2009-07-14 Waratah Pharmaceuticals Inc. Pharmaceutical composition consisting of rapamycine and gastrin 17(LEU15) and a method for treating diabetes
US7803766B2 (en) 2002-11-21 2010-09-28 Warath Pharmaceuticals, Inc Gastrin compositions and formulations, and methods of use and preparation
WO2008106779A1 (fr) * 2007-03-02 2008-09-12 Waratah Pharmaceuticals Inc. Composé de gastrine pour le traitement du diabète
WO2009039994A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009039995A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Big gastrine-i en tant qu'agent thérapeutique
CN107129538B (zh) * 2010-04-27 2021-07-16 西兰制药公司 Glp-1受体激动剂和胃泌素的肽缀合物及其用途
CN103003300A (zh) * 2010-04-27 2013-03-27 西兰制药公司 Glp-1受体激动剂和胃泌素的肽缀合物及其用途
CN103003300B (zh) * 2010-04-27 2017-06-09 西兰制药公司 Glp‑1受体激动剂和胃泌素的肽缀合物及其用途
JP2013525387A (ja) * 2010-04-27 2013-06-20 ジーランド ファーマ アクティーゼルスカブ Ｇｌｐ−１受容体作動薬とガストリンとのペプチド複合体及びその使用
US10406207B2 (en) 2010-04-27 2019-09-10 Zealand Pharma A/S Peptide conjugates of GLP-1 receptor agonists and gastrin and their use
WO2011134471A1 (fr) * 2010-04-27 2011-11-03 Zealand Pharma A/S Conjugués peptidiques d'antagonistes du récepteur de glp-1 et de gastrine, et leur utilisation
US20170281709A1 (en) * 2010-04-27 2017-10-05 Zealand Pharma A/S Peptide conjugates of glp-1 receptor agonists and gastrin and their use
US9089538B2 (en) 2010-04-27 2015-07-28 Zealand Pharma A/S Peptide conjugates of GLP-1 receptor agonists and gastrin and their use
CN107129538A (zh) * 2010-04-27 2017-09-05 西兰制药公司 Glp‑1受体激动剂和胃泌素的肽缀合物及其用途
AU2011247452B2 (en) * 2010-04-27 2016-03-17 Zealand Pharma A/S Peptide conjugates of GLP-1 receptor agonists and gastrin and their use
EA023925B1 (ru) * 2010-04-27 2016-07-29 Зилэнд Фарма А/С Пептидные конъюгаты агонистов рецептора glp-1 и их применение
US9649362B2 (en) 2010-04-27 2017-05-16 Zealand Pharma A/S Peptide conjugates of GLP-1 receptor agonists and gastrin and their use
EA028951B1 (ru) * 2011-11-03 2018-01-31 Зилэнд Фарма А/С Пептидные конъюгаты агониста рецептора гастрина и глюкагон подобного пептида 1
US9259477B2 (en) 2011-11-03 2016-02-16 Zealand Pharma A/S GLP-1 receptor agonist peptide gastrin conjugates
JP2015502918A (ja) * 2011-11-03 2015-01-29 ジーランド ファーマ アクティーゼルスカブ Ｇｌｐ−１受容体アゴニストペプチドガストリンコンジュゲート
US9861706B2 (en) 2011-11-03 2018-01-09 Zealand Pharma A/S GLP-1 receptor agonist peptide gastrin conjugates
CN104144704A (zh) * 2011-11-03 2014-11-12 西兰制药公司 Glp-1受体激动剂肽胃泌素缀合物
WO2013064669A1 (fr) * 2011-11-03 2013-05-10 Zealand Pharma A/S Conjugués de peptide agoniste du récepteur du glp-1 et de gastrine
WO2013098408A1 (fr) * 2011-12-30 2013-07-04 Zealand Pharma A/S Conjugués peptidiques agonistes des récepteurs de la cck et du glucagon
US11795204B2 (en) 2012-07-23 2023-10-24 Zealand Pharma A/S Glucagon analogues
US10253081B2 (en) 2012-09-17 2019-04-09 Zealand Pharma A/S Glucagon analogues
US9975939B2 (en) 2012-09-17 2018-05-22 Zealand Pharma A/S Glucagon analogues
US11884713B2 (en) 2013-10-17 2024-01-30 Zealand Pharma A/S Acylated glucagon analogues
US11034747B2 (en) 2013-10-17 2021-06-15 Zealand Pharma A/S Glucagon analogues and methods of use
US11091528B2 (en) 2013-10-17 2021-08-17 Zealand Pharma A/S Acylated glucagon analogues
US10457714B2 (en) 2013-10-17 2019-10-29 Zealand Pharma A/S Acylated glucagon analogues
US10131702B2 (en) 2013-11-06 2018-11-20 Zealand Pharma A/S Glucagon-GLP-1-GIP triple agonist compounds
US11008375B2 (en) 2013-11-06 2021-05-18 Zealand Pharma A/S GIP-GLP-1 dual agonist compounds and methods
US11111285B2 (en) 2013-11-06 2021-09-07 Zealand Pharma A/S Glucagon-GLP-1-GIP triple agonist compounds
US10093713B2 (en) 2013-11-06 2018-10-09 Zealand Pharma A/S GIP-GLP-1 dual agonist compounds and methods
US11001619B2 (en) 2014-10-29 2021-05-11 Zealand Pharma A/S GIP agonist compounds and methods
US10253078B2 (en) 2014-10-29 2019-04-09 Zealand Pharma A/S GIP agonist compounds and methods
US11814417B2 (en) 2014-10-29 2023-11-14 Zealand Pharma A/S GIP agonist compounds and methods
US10336802B2 (en) 2015-04-16 2019-07-02 Zealand Pharma A/S Acylated glucagon analogue
US11274136B2 (en) 2015-04-16 2022-03-15 Zealand Pharma A/S Acylated glucagon analogue
US10905745B2 (en) 2016-12-09 2021-02-02 Zealand Pharma A/S Acylated GLP-1/GLP-2 dual agonists
US11395847B2 (en) 2016-12-09 2022-07-26 Zealand Pharma A/S Acylated GLP-1/GLP-2 dual agonists
CN112759640A (zh) * 2020-12-09 2021-05-07 江苏师范大学 一类glp-1/胃泌素受体双重激动剂及其应用
CN112759640B (zh) * 2020-12-09 2023-09-08 江苏师范大学 一类glp-1/胃泌素受体双重激动剂及其应用

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