CN115594752A

CN115594752A - Long-acting double-agonist compound

Info

Publication number: CN115594752A
Application number: CN202110768870.3A
Authority: CN
Inventors: 周述靓; 王鹏; 邓岚
Original assignee: Chengdu Aoda Biotechnology Co ltd
Current assignee: Chengdu Aoda Biotechnology Co ltd
Priority date: 2021-07-07
Filing date: 2021-07-07
Publication date: 2023-01-13

Abstract

The invention relates to the field of medicine synthesis, and discloses a long-acting double-agonist compound. The tirapatide derivative is used for preparing a medicine composition for treating diseases, and the medicine composition is used for preparing medicines for treating at least one of type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorder, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular diseases, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcer, hepatic fibrosis diseases and pulmonary fibrosis diseases.

Description

Long-acting double-agonist compound

Technical Field

The invention relates to a long-acting double-agonist compound and application thereof, wherein the compound is a double incretin peptide analog compound for exciting a human glucose-dependent insulinotropic polypeptide (GIP) and a glucagon-like peptide-1 (GLP-l) receptor.

Background

GIP is a 42 amino acid gastrointestinal regulatory peptide that plays a physiological role in glucose homeostasis by stimulating insulin secretion from and protecting pancreatic beta cells in the presence of glucose. GLP-l is a 37 amino acid peptide that stimulates insulin secretion, protects pancreatic beta cells, and inhibits glucagon secretion, gastric emptying, and food intake, resulting in weight loss. GIP and GLP-l are known as incretins; incretin receptor signaling plays a key physiologically relevant role in glucose homeostasis. In normal physiology, GIP and GLP-1 are secreted from the intestinal tract after a meal, and these incretins enhance physiological responses to food, including satiety, insulin secretion, and nutrient handling.

The most common side effect of GLP-l compounds is that full-effect glycemic control and weight loss cannot be achieved with administration, whereas GIP alone has a very modest glucose lowering capacity in type 2 diabetics. Both native GIP and GLP-l can be rapidly inactivated by the ubiquitous protease DPP IV and therefore can only be used for short-term metabolic control.

It is reported in WO 2013/164483 and WO 2014/192284 that certain GIP/GLP-1 compounds exhibit both GIP and GLP-1 activity and that the compounds can be found to achieve better efficacy in glycemic control and weight loss.

The Tirzepatide is a GIP/GLP-1 compound, and because the bioactivity is relatively low and the clinical dosage is relatively high, the invention aims to search for derivatives with higher bioactivity and reduce the clinical dosage and corresponding side effects.

Disclosure of Invention

The invention provides a long-acting double agonist compound and application thereof, wherein the compound is a double incretin peptide analog compound for exciting human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-l) receptors.

To achieve the above objects, the present invention provides, in a first aspect, a compound of structure I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, a prodrug based on the compound, or any mixture thereof.

Tyr-AA1-Glu-Gly-Thr-AA2-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-AA3(R)-Ile-Ala-Gln-AA4-Ala-AA5-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA6

Structure I

AA1 in the structure I is Aib, or is Acpr, or is Acp, or is Acpe, or is Ach;

AA2 in structure I is Phe, or is N ^α -Me-Phe；

AA3 in structure I is Lys, or Orn, or Dab, or Dap;

AA4 in the structure I is Arg, or Cit, or Harg;

AA5 in structure I is Phe, or 1-Nal;

AA6 in Structure I is NH ₂ Or is OH;

r in structure I is HO ₂ C(CH ₂ ) _n1 CO-(γGlu) _n2 -(PEG _n3 (CH2) _n4 CO) _n5 -; or is HO ₂ C(CH ₂ ) _n1 CO-(γGlu) _n2 -(AA4) _n6 -：

Wherein: n1 is an integer of 10 to 20;

n2 is an integer of 1 to 5;

n3 is an integer from 1 to 30;

n4 is an integer from 1 to 5;

n5 is an integer from 1 to 5;

n6 is an integer from 1 to 10;

AA4 is Gly, or is Ser, or is Glu.

The invention also provides pharmaceutical compositions comprising a compound according to the invention and the use of a pharmaceutical composition comprising a compound of the invention for the preparation of a medicament for the treatment of a disease.

Preferably, the use of the pharmaceutical composition in the manufacture of a medicament for the treatment of at least one of type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcer, liver fibrosis diseases and pulmonary fibrosis diseases.

Preferably, the pharmaceutical composition is applied to the preparation of medicines for treating delayed drug effect of type II diabetes and/or preventing worsening of type II diabetes.

Preferably, the use of the pharmaceutical composition for the manufacture of a medicament for reducing food intake, reducing beta cell apoptosis, increasing islet beta cell function, increasing beta cell mass, and/or restoring glucose sensitivity to beta cells.

The invention still further provides methods of administering the compounds to a subject to modulate blood glucose in vivo.

Further details of the invention are set forth below, or some may be appreciated in embodiments of the invention.

Unless otherwise indicated, the quantities of the various ingredients, reaction conditions, and so forth used herein are to be construed in any case as "substantially" and "approximately". Accordingly, unless expressly stated otherwise, all numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in the respective experimental conditions.

Herein, when a chemical structural formula and a chemical name of a compound are ambiguous or ambiguous, the compound is exactly defined by the chemical structural formula. The compounds described herein may contain one or more chiral centers, and/or double bonds and the like, and stereoisomers, including isomers (e.g., geometric isomers), optical enantiomers, or diastereomers of the double bonds, may also be present. Accordingly, any chemical structure within the scope of the present disclosure, whether partial or complete, including similar structures as described above, includes all possible enantiomers and diastereomers of the compound, including any single stereoisomer (e.g., a single geometric isomer, a single enantiomer, or a single diastereomer), and any mixture of such stereoisomers. Mixtures of these racemates and stereoisomers may also be further resolved into the enantiomers or stereoisomers of their constituent members by those skilled in the art using non-stop separation techniques or methods of chiral molecular synthesis.

The compounds of formula I include, but are not limited to, optical isomers, racemates and/or other mixtures of these compounds. In the above case, a single enantiomer or diastereomer, such as an optical isomer, can be obtained by asymmetric synthesis or racemate resolution. Resolution of the racemates can be accomplished in a variety of ways, such as by recrystallization from resolution-assisting reagents, or by chromatography. In addition, the compounds of formula I also include cis and/or trans isomers with double bonds.

The compounds of the present invention include, but are not limited to, the compounds of formula I and all of their pharmaceutically acceptable different forms. The pharmaceutically acceptable different forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above and any mixtures of these forms.

The compound shown in the structure I provided by the invention has stable property, is not easily degraded by dipeptidyl peptidase IV (DPP-IV) in vivo, is a GIP/GLP-I dual agonist compound, and has obvious effects of reducing blood sugar and weight.

Detailed Description

The invention discloses a GIP/GLP-1 compound and application thereof, and a person skilled in the art can appropriately improve related parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the process of the present invention has been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the compounds and processes described herein, as well as other changes and combinations of the foregoing, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.

The Chinese names corresponding to the English abbreviations involved in the present invention are shown in the following table:

english abbreviation	Name of Chinese	English abbreviation	Name of Chinese
				Fmoc	9-fluorenylmethyloxycarbonyl radical	OtBu	Tert-butoxy radical
tBu	Tert-butyl radical	Boc	Boc-butoxy carbonyl group
				Trt	Trityl radical	Pbf	(2, 3-dihydro-2, 4,6, 7-pentamethylbenzofuran-5-yl) sulfonyl group
Ala	Alanine	Leu	Leucine
				Arg	Arginine	Lys	Lysine
Asn	Asparagine	Phe	Phenylalanine
				Asp	Aspartic acid	Pro	Proline
Cys	Cysteine	Ser	Serine
				Gln	Glutamine	Thr	Threonine
Glu	Glutamic acid	Trp	Tryptophan
				Gly	Glycine	Tyr	Tyrosine
His	Histidine	Val	Valine
				Ile	Isoleucine	Dab	2, 4-diaminobutyric acid
Dap	2, 3-diaminopropionic acid	Dah	2, 7-Diaminoheptanoic acid
				Orn	Ornithine	Aib	Aminoisobutyric acid

EXAMPLE 1 preparation of Compound 1

Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys(PEG ₅ CH ₂ CO-Gamma Glu-20 Alkanedioic acid) -Ile-Ala-Gln-Arg-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-NH ₂

The preparation method comprises the following steps: preparing peptide resin by adopting a solid-phase polypeptide synthesis method, carrying out acidolysis on the peptide resin to obtain a crude product, and finally purifying the crude product to obtain a pure product; the step of preparing the peptide resin by the solid-phase polypeptide synthesis method is to sequentially insert corresponding protective amino acids or fragments in the following sequences on a carrier resin by the solid-phase coupling synthesis method to prepare the peptide resin:

in the preparation method, the dosage of the Fmoc-protected amino acid or the protected amino acid fragment is 1.2 to 6 times of the total mole number of the charged resin; preferably 2.5 to 3.5 times.

In the above preparation method, the substitution value of the carrier resin is 0.2 to 1.0mmol/g resin, and preferably 0.3 to 0.5mmol/g resin.

As a preferable embodiment of the present invention, the solid-phase coupling synthesis method is: and (3) removing the Fmoc protecting group from the protected amino acid-resin obtained in the previous step of reaction, and then carrying out coupling reaction with the next protected amino acid. The deprotection time of the Fmoc protection removal is 10 to 60 minutes, and preferably 15 to 25 minutes. The coupling reaction time is 60 to 300 minutes, preferably 100 to 140 minutes.

The coupling reaction needs to add a condensation reagent, and the condensation reagent is selected from one of DIC (N, N-diisopropyl carbodiimide), N, N-dicyclohexylcarbodiimide, benzotriazole-1-yl-oxy tripyrrolidinyl phosphorus hexafluorophosphate, 2- (7-aza-1H-benzotriazole-1-yl) -1, 3-tetramethylurea hexafluorophosphate, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate or O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate; preferred is N, N-diisopropylcarbodiimide. The molar consumption of the condensation reagent is 1.2 to 6 times, preferably 2.5 to 3.5 times of the total molar number of the amino in the amino resin.

The coupling reaction needs to add an activating reagent, wherein the activating reagent is selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, and 1-hydroxybenzotriazole is preferred. The amount of the activating agent is 1.2 to 6 times, preferably 2.5 to 3.5 times the total molar number of the amino groups in the amino resin.

In a preferred embodiment of the present invention, the Fmoc deprotection reagent is a mixed solution of PIP/DMF (piperidine/N, N-dimethylformamide) and the mixed solution contains 10-30% (V) piperidine. The dosage of the Fmoc-removing protective reagent is 5-15 mL per gram of amino resin, and is preferably 8-12 mL per gram of amino resin.

Preferably, the peptide resin is subjected to acidolysis while removing the resin and side chain protecting groups to obtain a crude product:

more preferably, the acidolysis agent used in the acidolysis of the peptide resin is a mixed solvent of trifluoroacetic acid (TFA), 1, 2-Ethanedithiol (EDT) and water, and the volume ratio of the mixed solvent is as follows: 80-95% of TFA, 1-10% of EDT and the balance of water.

More preferably, the volume ratio of the mixed solvent is: 89 to 91 percent of TFA, 4 to 6 percent of EDT and the balance of water. Optimally, the volume ratio of the mixed solvent is as follows: TFA 90%, EDT 5%, balance water.

The dosage of the acidolysis agent is 4-15 mL per gram of the peptide resin; preferably, 7 to 10mL of acid hydrolysis agent per gram of peptide resin is required.

The time for the cleavage with the acidolysis agent is 1 to 6 hours, preferably 3 to 4 hours, at room temperature.

Further, the crude product is purified by high performance liquid chromatography and freeze-dried to obtain a pure product.

1. Synthesis of peptide resins

Rink Amide BHHA resin is used as carrier resin, and is coupled with protected amino acid shown in the following table in sequence through Fmoc protection removal and coupling reaction to prepare peptide resin. The protected amino acids used in this example correspond to the protected amino acids shown below:

(1) 1 st protected amino acid incorporated into the backbone

Dissolving 0.03mol of the 1 st protected amino acid and 0.03mol of HOBt in a proper amount of DMF; and slowly adding 0.03mol of DIC into the protected amino acid DMF solution under stirring, and reacting for 30 minutes under stirring at room temperature to obtain an activated protected amino acid solution for later use.

0.01mol of Rink amide MBHA resin (substitution value about 0.4 mmol/g) was deprotected with 20% PIP/DMF solution for 25 minutes, and washing and filtration gave Fmoc-removed resin.

And adding the activated 1 st protected amino acid solution into the Fmoc-removed resin, performing coupling reaction for 60-300 minutes, filtering and washing to obtain the resin containing 1 protected amino acid.

(2) The 2 nd to 39 th protected amino acids are connected into the main chain

And sequentially inoculating the corresponding 2 nd to 39 th protected amino acids by the same method for inoculating the 1 st protected amino acid of the main chain to obtain the resin containing 39 amino acids of the main chain.

(3) Side chain insertion of the 1 st protected amino acid

Taking 0.03mol of side chain 1 st protected amino acid and 0.03mol of HOBt, and dissolving with a proper amount of DMF; and slowly adding 0.03mol of DIC into the protected amino acid DMF solution under stirring, and reacting for 30 minutes under stirring at room temperature to obtain the activated protected amino acid solution.

2.5mmol of tetratriphenylphosphine palladium and 25mmol of phenylsilane are dissolved by using a proper amount of dichloromethane, deprotection is carried out for 4 hours, and the solution is filtered and washed to obtain a resin with Alloc removed for later use.

Adding the side chain 1 st protected amino acid solution after activation into the Alloc-removed resin, performing coupling reaction for 60-300 minutes, filtering and washing to obtain the side chain 1 st protected amino acid-containing resin.

(4) By inserting other protected amino acids or mono-protected fatty acids into the side chain

And sequentially inoculating the protected amino acid and the mono-protected fatty acid corresponding to the side chain by adopting the same method for inoculating the 1 st protected amino acid into the main chain to obtain the peptide resin.

2. Preparation of crude product

Adding a cleavage reagent (10 mL of cleavage reagent/g of resin) with a volume ratio of TFA: water: EDT = 95: 5 into the peptide resin, uniformly stirring, stirring at room temperature for reaction for 3 hours, filtering a reaction mixture by using a sand core funnel, collecting a filtrate, washing the resin with a small amount of TFA for 3 times, combining the filtrates, concentrating under reduced pressure, adding anhydrous ether for precipitation, washing the precipitate with anhydrous ether for 3 times, and drying to obtain a white-like powder which is a crude product.

3. Preparation of the pure product

Mixing the crude product with water, stirring, adjusting pH to 8.0 with ammonia water to dissolve completely, filtering the solution with 0.45 μm mixed microporous membrane, and purifying;

purifying by high performance liquid chromatography, wherein the chromatographic packing for purification is 10 μm reversed phase C18, the mobile phase system is 0.1% TFA/aqueous solution-0.1% TFA/acetonitrile solution, the flow rate of the chromatographic column of 30mm 250mm is 20mL/min, eluting by a gradient system, purifying by circulating sample injection, sampling the crude product solution in the chromatographic column, starting the mobile phase elution, collecting the main peak, evaporating off acetonitrile, and obtaining a purified intermediate concentrated solution;

filtering the purified intermediate concentrated solution with 0.45 μm filter membrane for use, and performing salt exchange by high performance liquid chromatography, wherein the mobile phase system is 1% acetic acid/water solution-acetonitrile, and the purification chromatographic packing is 10 μm reversed phase C18, 30mm × 250mm chromatographic column flow rate is 20mL/min (corresponding flow rate can be adjusted according to chromatographic columns of different specifications); the method comprises the steps of adopting a gradient elution and circulation loading method, loading a sample into a chromatographic column, starting mobile phase elution, collecting a map, observing the change of the absorbance, collecting a main salt exchange peak, detecting the purity by using an analysis liquid phase, combining main salt exchange peak solutions, concentrating under reduced pressure to obtain a pure acetic acid aqueous solution, and freeze-drying to obtain 8.6g of a pure product, wherein the purity is 97.9 percent, and the total yield is 17.8 percent. The molecular weight is 4828.5 (100% M + H).

EXAMPLE 2 preparation of Compound 2

Tyr-Aib-Glu-Gly-Thr-N ^α -Me-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys(PEG ₅ CH ₂ CO-gamma Glu-20 alkanedioic acid) -Ile-Ala-Gln-Arg-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH ₂

The procedure is as in example 1, using the protected amino acids as follows:

6.1g of pure product is obtained, the purity is 97.2 percent, and the total yield is 12.6 percent. The molecular weight is 4842.6 (100% by weight M + H).

EXAMPLE 3 preparation of Compound 3

Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys (AEEA-AEEA-gamma Glu-20 alkanedioic acid) -Ile-Ala-Gln-Arg-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Gly-Gly-Ala-Pro-Pro-Ser-NH ₂

The procedure is as in example 1, using the protected amino acids as follows:

7.1g of pure product is obtained, the purity is 97.6 percent, and the total yield is 14.7 percent. The molecular weight is 4841.6 (100% M + H).

EXAMPLE 4 preparation of Compound 4

Tyr-Aib-Glu-Gly-Thr-N ^α -Me-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys (AEEA-AEEA-Gamma Glu-20 alkanedioic acid) -Ile-Ala-Gln-Arg-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-NH ₂

The procedure is as in example 1, using the protected amino acids as in the following table:

5.7g of pure product is obtained, the purity is 96.9 percent, and the total yield is 11.7 percent. The molecular weight is 4855.6 (100% by weight M + H).

Example 5 measurement of GLP-1 Activity

1. Measurement method

GLP-1R, stimulated by its specific agonist, activates the intracellular adenylate cyclase pathway, raises cAMP levels, and ultimately leads to the production and release of insulin. A cell strain which is stably transfected with GLP-1R is stimulated by an object to be tested to ensure that the intracellular cAMP level of the cell is rapidly increased, and the Relative Light Unit (RLU) after each dose of stimulated cells is measured by a chemiluminescence method to further calculate the EC50 of the agonist, wherein the activity measuring method is a GLP-1 receptor agonist activity detecting method which is commonly used at home and abroad at present.

Adopting CHO-K1 cell strain for stably expressing GLP-1R, stimulating stable cells with agonists of different concentrations, measuring relative light units of the stimulated cells after each dose, and taking Tirzepatide as a reference substance to obtain EC of the agonist ₅₀ The value is obtained.

2. Measurement results

The results of the measurements are given in the following table:

compound (I)	GLP-1 Activity [ EC ₅₀ (pmol)】
		Tirzepatide	153.7
Compound 1	77.0
		Compound 2	95.6
Compound 3	122.9
		Compound 4	104.3

Example 6 assay of GIP Activity

1. Measurement method

GIPR, stimulated by its specific agonist, activates the intracellular adenylate cyclase pathway, elevating cAMP levels, ultimately leading to the production and release of insulin. A cell strain which is stably transfected with GIPR is stimulated by an analyte to be detected, so that the intracellular cAMP level of the cell is rapidly increased, and the Relative Light Unit (RLU) after each dose of stimulated cells is determined by a chemiluminescence method, so that the EC50 of the agonist is further calculated.

Adopting CHO-K1 cell strain capable of stably expressing GIPR, stimulating stable transformed cells with agonists of different concentrations, measuring relative light unit of stimulated cells of each dose, and taking Tirzepatide as a reference substance to obtain EC of the agonist ₅₀ The value is obtained.

2. Measurement results

The results of the assay are shown in the following table:

compound (I)	GIP activity [ EC ₅₀ (pmol)】
		Tirzepatide	48.2
Compound 1	50.3
		Compound 2	55.6
Compound 3	66.3
		Compound 4	70.2

Example 7 preliminary PK assay

The test animal is a cynomolgus monkey, is subcutaneously administrated, the dose is 0.2mg/kg, and the test animal is intravenously bled 5min, 10min, 30min, 45min, 1h, 2h, 3h, 6h, 8h, 24h, 32h, 48h, 72h, 96h, 144h and 192h after the administration respectively before the administration (0 h) and before each administration after the administration (0 h), and plasma samples are centrifugally separated, and the blood concentration of corresponding compounds in the plasma samples is respectively measured by a liquid chromatography-mass spectrometry method to obtain the primary PK parameters of Subcutaneous (SC) administration of the compounds.

Claims

1. A long-acting dual agonist compound having the structural formula i:

Tyr-AA1-Glu-Gly-Thr-AA2-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-

Asp-AA3(R)-Ile-Ala-Gln-AA4-Ala-AA5-Val-Gln-Trp-Leu-Ile-

Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA6

structure I

AA1 in the structure I is Aib, or is Acpr, or is Acp, or is Acpe, or is Ach;

AA2 in the structure I is Phe or N ^α -Me-Phe；

AA3 in structure I is Lys, or Orn, or Dab, or Dap;

AA4 in the structure I is Arg, or Cit, or Harg;

AA5 in structure I is Phe, or 1-Nal;

AA6 in Structure I is NH ₂ Or is OH;

Wherein: n1 is an integer of 10 to 20;

n2 is an integer from 1 to 5;

n3 is an integer from 1 to 30;

n4 is an integer from 1 to 5;

n5 is an integer from 1 to 5;

n6 is an integer from 1 to 10;

AA4 is Gly, or is Ser, or is Glu.

2. A long-acting dual agonist compound according to claim 1, comprising a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, a prodrug thereof, or a mixture of any of the foregoing.

3. A long-acting dual agonist compound according to claim 1 and claim 2 for use in the preparation of a pharmaceutical composition for the treatment of a disease.

4. The pharmaceutical composition according to claim 3, for use in the manufacture of a medicament for the treatment of at least one of type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcer, liver fibrosis diseases and pulmonary fibrosis diseases.

5. The pharmaceutical composition according to claim 4, for use in the preparation of a medicament for the treatment of delayed drug action and/or prevention of worsening of type II diabetes.

6. Use of a pharmaceutical composition according to claim 6 for the manufacture of a medicament for reducing food intake, reducing beta cell apoptosis, increasing islet beta cell function, increasing beta cell mass, and/or restoring glucose sensitivity to beta cells.

7. The long-acting dual agonist compound of claim 1, comprising the compound for use in a method of modulating blood glucose in a body.