CN117229364A - GIP-GLP-1 double-agonist compound - Google Patents

GIP-GLP-1 double-agonist compound Download PDF

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CN117229364A
CN117229364A CN202210630257.XA CN202210630257A CN117229364A CN 117229364 A CN117229364 A CN 117229364A CN 202210630257 A CN202210630257 A CN 202210630257A CN 117229364 A CN117229364 A CN 117229364A
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glp
integer
gip
agonist compound
pharmaceutical composition
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周述靓
于海宁
王鹏
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Chengdu Aoda Biotechnology Co ltd
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Chengdu Aoda Biotechnology Co ltd
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Abstract

The invention relates to the field of medicine synthesis, and discloses a GIP-GLP-1 double-agonist compound. The GIP-GLP-1 dual agonist compound of the invention is used for preparing a pharmaceutical composition for treating at least one of the following diseases, wherein the diseases comprise type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive dysfunction, 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

GIP-GLP-1 double-agonist compound
Technical Field
The present invention relates to a GIP-GLP-1 dual agonist compound and its application, said compound is a kind of double-intestinal insulinotropic peptide mimic compound for exciting human glucose-dependent insulinotropic polypeptide (GIP) and 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 pancreatic beta cells 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 management.
The most common side effect of GLP-l compounds is that administration does not achieve full glycemic control and weight loss, whereas GIP alone has 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 was 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 glycemic control and weight loss efficacy.
Tirzepatide is a GIP/GLP-1 compound, and because the biological activity is relatively low and the clinical use dosage is relatively high, the invention aims to seek derivatives with higher biological activity and reduce the clinical use dosage and corresponding side effects.
Disclosure of Invention
The invention provides a GIP-GLP-1 dual agonist compound and application thereof, wherein the compound is a dual incretin peptide mimetic compound for exciting human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-l) receptor.
To achieve the above object, the present invention provides a compound of the formula I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, a prodrug based on the compound, or a mixture of any of the above forms.
AA1 in the structure I is Gly-Gy or 5-Ava;
AA2 in structure I is NH 2 Or is OH;
m1 in structure I is an integer from 1 to 10;
m2 in structure I is an integer from 1 to 10;
r in structure I is HO 2 C(CH 2 ) n1 CO-(AA3) n2 -(PEG n3 (CH 2 ) n4 CO) n5 -; or HO 2 C(CH 2 ) n1 CO-(AA3) n2 -(AA4) n6 -: wherein:
n1 is an integer from 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;
AA3 is γglu, or εlys, or β -Ala, or γ -aminobutyric acid, or 5-Ava;
AA4 is Gly, or Ser, or Asp, or Glu, or Ada, or Apm, or Asu.
The invention also provides a pharmaceutical composition comprising the compound according to the invention, and the use of the pharmaceutical composition of the compound for preparing a medicament for treating a disease.
Preferably, the pharmaceutical composition is used for the preparation 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 diseases, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcers, liver fibrosis diseases and pulmonary fibrosis diseases.
Preferably, the pharmaceutical composition is applied to the preparation of medicines for treating drug effect delay of type II diabetes and/or preventing exacerbation of type II diabetes.
Preferably, the pharmaceutical composition is used for preparing a medicament for reducing food intake, reducing beta cell apoptosis, increasing islet beta cell function, increasing beta cell mass and/or reverting sensitivity of glucose to beta cells.
The invention still further provides methods of administering the compounds to a subject to regulate blood glucose in vivo.
Further details of the invention are set forth in the accompanying drawings and the description below, or may be learned by practice of the invention.
Unless otherwise indicated, the amounts of the various components, reaction conditions, and the like, are used herein and are to be construed in any sense as "generally", "about". Accordingly, unless explicitly indicated otherwise, the numerical parameters set forth in the following claims are approximations that may vary depending upon the standard deviation employed under the particular circumstances.
Herein, when the chemical structural formula and chemical name of a compound are divergent or ambiguous, the compound is defined exactly 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 of double bonds (such as geometric isomers), optical enantiomers or diastereomers, may also be present. Accordingly, any chemical structure within the scope of the description herein, whether partial or whole containing such structures, 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 mixtures of any of these isomers. These racemic isomers and mixtures of stereoisomers may also be resolved further into their constituent enantiomers or stereoisomers by methods known to those skilled in the art using continuous separation techniques or chiral molecule 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 cases, single enantiomers or diastereomers, such as optical isomers, may be obtained by asymmetric synthesis or resolution of racemates. Resolution of the racemate can be accomplished in various ways, such as recrystallization with conventional resolution-aiding reagents, or by chromatographic methods. In addition, the compounds of the formula I also contain 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 various pharmaceutically acceptable forms. Pharmaceutically useful different forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above, and mixtures of any of these forms.
The compound shown in the structure I provided by the invention has stable properties, is not easily degraded by dipeptidyl peptidase IV (DPP-IV) in vivo, is a GIP/GLP-I double-agonist compound, and has remarkable effects of reducing blood glucose and body 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 of the present disclosure. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the process of the present invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the compounds and methods of preparation described herein, or in appropriate combinations, without departing from the spirit and scope of the invention.
The Chinese names corresponding to the English abbreviations in the invention are shown in the following table:
english abbreviations Chinese name English abbreviations Chinese name
Fmoc 9-fluorenylmethoxycarbonyl OtBu Tert-butoxy radical
tBu Tert-butyl group Boc Boc acid tert-butyl ester
Trt Trityl radical Pbf (2, 3-dihydro-2, 4,6, 7-pentamethylbenzofuran-5-yl) sulfonyl
Ala Alanine (Ala) Leu Leucine (leucine)
Arg Arginine (Arg) Lys Lysine
Asn Asparagine derivatives Phe Phenylalanine (Phe)
Asp Aspartic acid Pro Proline (proline)
Cys Cysteine (S) Ser Serine (serine)
Gln Glutamine Thr Threonine (Thr)
Glu Glutamic acid Trp Tryptophan
Gly Glycine (Gly) Tyr Tyrosine
His Histidine Val Valine (valine)
Ile Isoleucine (Ile) Dab 2, 4-diaminobutyric acid
5-Ava 5-Aminopentanoic acid Orn Ornithine
Aib Amino isobutyric acid Dah 2, 7-diaminoheptanoic acid
Dap 2, 3-diaminopropionic acid Dao 2, 8-diamino octanoic acid
Ada 2-aminoadipic acid Apm 2-Aminopimelic acid
Asu 2-amino-suberic acid
Example 1 preparation of Compounds
The preparation method comprises the following steps: preparing peptide resin by adopting a solid-phase polypeptide synthesis method, acidolysis is carried out on the peptide resin to obtain a crude product, and finally, the crude product is purified to obtain a pure product; wherein the step of preparing peptide resin by solid phase polypeptide synthesis method comprises the steps of sequentially accessing corresponding protected amino acid or fragment in polypeptide sequence on carrier resin by solid phase coupling synthesis method, and preparing peptide resin:
in the preparation method, the dosage of the Fmoc-protected amino acid or the protected amino acid fragment is 1.2-6 times of the total mole number of the resin; preferably 2.5 to 3.5 times.
In the preparation method, the substitution value of the carrier resin is 0.2-1.0 mmol/g resin, and the preferred substitution value is 0.3-0.5 mmol/g resin.
As a preferred scheme of the invention, the solid phase coupling synthesis method is as follows: the protected amino acid-resin obtained in the previous step is subjected to Fmoc protecting group removal and then is subjected to coupling reaction with the next protected amino acid. The deprotection time for Fmoc deprotection is 10 to 60 minutes, 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, wherein the condensation reagent is selected from DIC (N, N-diisopropyl carbodiimide), N, N-dicyclohexylcarbodiimide, benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate, 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate or O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate; n, N-diisopropylcarbodiimide is preferred. The molar amount of the condensing agent is 1.2 to 6 times, preferably 2.5 to 3.5 times, the total molar amount of the amino groups in the amino resin.
The coupling reaction needs to add an activating reagent, and the activating reagent is selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, and is preferably 1-hydroxybenzotriazole. The amount of the activating agent to be used is 1.2 to 6 times, preferably 2.5 to 3.5 times, the total mole number of the amino groups in the amino resin.
As a preferred scheme of the invention, the Fmoc protection removing reagent is PIP/DMF (piperidine/N, N-dimethylformamide) mixed solution, and the mixed solution contains 10-30% (V) of piperidine. The Fmoc-removing protective agent is used in an amount of 5-15 mL per gram of amino resin, preferably 8-12 mL per gram of amino resin.
Preferably, the peptide resin is subjected to acidolysis and simultaneously the resin and side chain protecting group are removed to obtain a crude product:
further preferably, the acidolysis agent used in 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.
Still more preferably, the volume ratio of the mixed solvent is: 89-91% TFA, 4-6% EDT and the balance 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 of acidolysis agent required by each gram of peptide resin; preferably, 7 to 10mL of acidolysis agent is required per gram of peptide resin.
The time for cleavage with acidolysis agent is 1 to 6 hours, preferably 3 to 4 hours, at room temperature.
Further, purifying the crude product by high performance liquid chromatography, and lyophilizing to obtain pure product.
1. Synthesis of peptide resins
And (3) using Rink Amide BHHA resin as carrier resin, and coupling with protected amino acid corresponding to the polypeptide sequence sequentially through Fmoc protection removal and coupling reaction to prepare the peptide resin.
(1) Access to backbone 1 st protected amino acid
Taking 0.03mol of 1 st protected amino acid and 0.03mol of HOBt, and dissolving the 1 st protected amino acid and the HOBt with a proper amount of DMF; and (3) adding 0.03mol of DIC into the protected amino acid DMF solution slowly under stirring, and stirring and reacting for 30 minutes in a room temperature environment 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 taken and deprotected with 20% PIP/DMF solution for 25 min, washed and filtered to give Fmoc-removed resin.
And adding the activated 1 st protected amino acid solution into Fmoc-removed resin, performing coupling reaction for 60-300 minutes, and filtering and washing to obtain the resin containing 1 protected amino acid.
(2) Access backbone protected amino acids
The same method of accessing the 1 st protected amino acid of the main chain is adopted, and the protected amino acids corresponding to the corresponding polypeptide sequences are sequentially accessed to obtain the resin containing the main chain amino acid.
The protective amino acid corresponding to Tyr at position 1 is Boc-Tyr (tBu).
The protecting amino acid corresponding to Lys at position 16 is Fmoc-Lys (Alloc).
The protecting amino acid corresponding to Lys at position 20 is Fmoc-Lys (Mtt).
(3) Access Compound 1
Taking 0.03mol of compound 1 and 0.03mol of HOBt, and dissolving the compound with a proper amount of DMF; and adding 0.03mol of DIC into the protected amino acid DMF solution under stirring, and stirring and reacting for 30 minutes in a room temperature environment to obtain an activated protected amino acid solution.
The Mtt protecting group of the 20 th Lys side chain is removed by 50% hexafluoroisopropanol/dichloromethane solution for 30 min each time, and the total time is 5 times, and the resin with the Mtt removed is obtained for standby.
And adding the activated compound 1 solution into the Mtt-removed resin, performing coupling reaction for 60-300 minutes, and filtering and washing to obtain the resin containing the 1 st protected amino acid of the side chain.
(4) Cyclization
5mmol of tetraphenylphosphine palladium and 50mmol of phenylsilane are taken, dissolved by a proper amount of dichloromethane, and the Alloc and All protecting groups are removed for 8 hours, filtered and washed to obtain resin with Alloc and All removed for standby.
Taking 0.03mol of HOBt, and dissolving with a proper amount of DMF; another 0.03mol DIC is taken and dissolved by a proper amount of DMF; adding the mixture into the dealloc resin under stirring, carrying out coupling reaction for 60-300 minutes, filtering and washing to obtain cyclized resin.
(5) Access to side-chain protected amino acids or mono-protected fatty acids
The cyclized resin was taken and Fmoc-protected with 20% PIP/DMF solution for 25 min for compound 1, and the Fmoc-removed resin was obtained by washing and filtration.
The same method of accessing the 1 st protected amino acid of the main chain is adopted, and the protected amino acid and the single protected fatty acid corresponding to the side chain are sequentially accessed to obtain the peptide resin.
2. Preparation of crude product
Adding a cracking reagent (10 mL/g resin) with a volume ratio of TFA to water to EDT=95 to 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 filtrate, washing the resin with a small amount of TFA for 3 times, combining the filtrates, concentrating under reduced pressure, adding anhydrous diethyl ether for precipitation, washing the precipitation with anhydrous diethyl ether for 3 times, and pumping to obtain white-like powder which is a crude product.
3. Preparation of pure product
Mixing the crude product with water, 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 reverse phase C18 with the size of 10 μm, the mobile phase system is 0.1% TFA/water solution-0.1% TFA/acetonitrile solution, the flow rate of a chromatographic column with the size of 30mm is 250mm is 20mL/min, eluting by a gradient system, circularly sampling and purifying, sampling the crude product solution into the chromatographic column, starting mobile phase eluting, collecting main peaks, evaporating acetonitrile, and obtaining the purified intermediate concentrated solution.
Filtering the purified intermediate concentrate with 0.45 μm filter membrane for use, changing salt by high performance liquid chromatography, wherein the mobile phase system is 1% acetic acid/water solution-acetonitrile, the chromatographic column flow rate of purification column is 20mL/min (corresponding flow rate can be adjusted according to chromatographic columns of different specifications) with reversed phase C18 of 10 μm and 30mm x 250 mm; adopting a gradient elution and cyclic loading method, loading in a chromatographic column, starting mobile phase elution, collecting a spectrum, observing the change of absorbance, collecting a salt-exchange main peak, analyzing the liquid phase to detect the purity, combining the salt-exchange main peak solutions, concentrating under reduced pressure to obtain a pure acetic acid aqueous solution, and freeze-drying to obtain the pure peptide.
The following compounds were synthesized using the above procedure:
EXAMPLE 2 determination of GLP-1 Activity
1. Measurement method
GLP-1R, upon stimulation with its specific agonist, activates the intracellular adenylate cyclase pathway, elevating cAMP levels, ultimately leading to insulin production and release. The cell strain transfected with GLP-1R stably is stimulated by the to-be-detected substance, so that the intracellular cAMP level of the cell is rapidly increased, the Relative Light Unit (RLU) of the stimulated cell at each dose is measured by a chemiluminescence method, and then the EC50 of the agonist is calculated, and the activity measuring method is a current universal GLP-1 receptor agonist activity measuring method at home and abroad.
The EC of the agonist is calculated by using CHO-K1 cell lines stably expressing GLP-1R, stimulating stable transformed cells with different concentrations of the agonist and measuring the relative light units of the stimulated cells at each dose 50 Values.
2. Measurement results
The measurement results are shown in the following table:
compounds of formula (I) GLP-1 Activity [ EC 50 (pmol)】
Tirzepatide 145.6
AOD243903 47.1
AOD243904 51.6
AOD243905 55.3
AOD243906 50.3
Example 3 determination of GIP Activity
1. Measurement method
GIPR, upon stimulation with its specific agonist, activates the intracellular adenylate cyclase pathway, elevating cAMP levels, ultimately leading to insulin production and release. The cell strain stably transfected with the GIPR is stimulated by the to-be-detected substance, so that the intracellular cAMP level of the cell is rapidly increased, the Relative Light Unit (RLU) of the stimulated cell at each dose is measured by a chemiluminescence method, and then the EC50 of the agonist is calculated.
The EC of the agonist is calculated by using CHO-K1 cell lines stably expressing GIPR, stimulating stable transformed cells with different concentrations of the agonist and measuring the relative light units of the stimulated cells at each dose 50 Values.
2. Measurement results
The measurement results are shown in the following table:
compounds of formula (I) GIP Activity [ EC 50 (pmol)】
Tirzepatide 42.6
AOD243903 30.9
AOD243904 24.0
AOD243905 28.4
AOD243906 29.7

Claims (7)

1. A GIP-GLP-1 dual agonist compound having the structural formula i:
AA1 in the structure I is Gly-Gy or 5-Ava;
AA2 in structure I is NH 2 Or is OH;
m1 in structure I is an integer from 1 to 10;
m2 in structure I is an integer from 1 to 10;
r in structure I is HO 2 C(CH 2 ) n1 CO-(AA3) n2 -(PEG n3 (CH 2 ) n4 CO) n5 -; or HO 2 C(CH 2 ) n1 CO-(AA3) n2 -(AA4) n6 -：
Wherein: n1 is an integer from 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;
AA3 is γglu, or εlys, or β -Ala, or γ -aminobutyric acid, or 5-Ava;
AA4 is Gly, or Ser, or Asp, or Glu, or Ada, or Apm, or Asu.
2. A GIP-GLP-1 dual agonist compound according to claim 1, comprising a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, based on a prodrug thereof, or a mixture of any of the foregoing forms.
3. A GIP-GLP-1 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. A 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 diseases, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcers, liver fibrosis diseases and pulmonary fibrosis diseases.
5. The pharmaceutical composition according to claim 4, for use in the manufacture of a medicament for the treatment of delayed onset of drug effect and/or prevention of exacerbation of type II diabetes.
6. The 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. A GIP-GLP-1 dual agonist compound according to claim 1, comprising the compound for use in a method of modulating blood glucose in vivo.
CN202210630257.XA 2022-06-06 2022-06-06 GIP-GLP-1 double-agonist compound Pending CN117229364A (en)

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