Use of PPARα / δ dual agonist in treatment of polycystic kidney disease

Abstract

The use of a PPARα / δ dual agonist in the treatment of polycystic kidney disease. In an acute ADPKD mouse administration model, compared with a model group and a tolvaptan (TVP) control group, mice which received treatment using dual-receptor agonist compounds, such as DA002S, DA002S / V1 and GFT505, exhibited a reduction in kidney volume and a significantly decreased kidney weight index; moreover, after administration, the mice exhibited significantly reduced renal cysticity index (cyst area), suggesting that cyst development is inhibited. The in-vivo efficacy of DA002S and DA002S / V1 is superior to that of tolvaptan (TVP) at the same dose, thus indicating that the PPARα / δ dual agonist compound can inhibit the progression of polycystic kidney disease, and has good in-vivo efficacy for polycystic kidney disease.

Description

Application of PPARα / δ dual agonists in the treatment of polycystic kidney disease Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to the application of a PPARα / δ dual agonist in the treatment of polycystic kidney disease. Background Art

[0002] PPARs, or peroxisome proliferator-activated receptors, were first discovered in 1990 and belong to the type II hormone receptor superfamily. They are essentially ligand-regulated transcription factors, divided into three subtypes: α, δ (β), and γ (γ1, γ2). When PPARs bind to agonists, they form heterodimers with retinoid X receptors (RXRs), bind to peroxisome proliferator response elements (PPREs), and initiate transcription of downstream target genes.

[0003] PKD is polycystic kidney disease, also known as Potter (I) syndrome, Perlmann syndrome, congenital renal cystic tumor disease, cystic kidney, bilateral renal agenesis syndrome, benign multilocular cystic kidney tumor, and polycystic disease. There are two types of polycystic kidney disease: autosomal recessive (infantile) polycystic kidney disease (ARPKD), which develops in infancy and is clinically rare; and autosomal dominant (adult-onset) polycystic kidney disease (ADPKD), which is often discovered in young and middle-aged adults but can also develop at any age. The gene mutation sites and the PKD associated with them are as follows:

[0004] Current treatments and medications for PKD are unable to fully control disease progression, and the medical outcome is kidney transplantation or death from renal failure. Currently, the only drug approved by the European Union and the FDA to slow the progression of PKD is the vasopressin V2 receptor antagonist tolvaptan. This drug is indicated for the treatment of clinically significant hypervolemic or normovolemic hyponatremia (blood sodium concentration <125 mEq / L, or subtle but symptomatic hyponatremia with poor response to fluid restriction), including patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). However, it has not yet been approved by the China National Medical Products Administration (NMPA) for the treatment of PKD. Due to the potential for frequent and severe adverse reactions such as liver damage, dehydration, and gout, it is primarily used in the preparatory setting for end-stage renal transplantation. Currently, there is an urgent need for new PKD treatments.

[0005] Summary of the Invention

[0006] Purpose of the invention: In view of the lack of effective clinical treatment for polycystic kidney disease (PKD) in the existing technology, the present invention proposes for the first time a new medical use of PPARα / δ dual agonists in the treatment of polycystic kidney disease.

[0007] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating polycystic kidney disease (PKD).

[0008] Technical solution: In order to achieve the above objectives, the present invention provides the use of a PPARα / δ dual agonist or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating polycystic kidney disease (PKD).

[0009] The polycystic kidney disease includes autosomal dominant (adult-type) polycystic kidney disease (ADPKD) and autosomal recessive (infantile-type) polycystic kidney disease (ARPKD).

[0010] Wherein, the PPARα / δ dual agonist includes any one of the protected compounds in the following documents or patents: (1) European Journal of Pharmacology 882(2020)173300; (2) Bioorganic Chemistry 99(2020)103803; (3) European Journal of Medicinal Chemistry 218(2021)113388; (4) Bioorganic & Medicinal Chemistry 24(2016)5455–5461; (5) Bioorganic & Medicinal Chemistry Letters 16(2006)554–558; (6) Chemistry & Biology December 1997.4:909-918, ACS Med.Chem.Lett.2019,10,1068-1073;(7)PCT patent PCTCN2022072221);(8)PCT patent PCTCN2022141359;(9)PCT patent PCTCN2024072800.

[0011] Wherein, the PPARα / δ dual agonist is selected from any one of the following compounds:

[0012] Preferably, the PPARα / δ dual agonist includes any one of 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid, 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid, and 2-[2,6-dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methylpropanoic acid.

[0013] The PPARα / δ dual agonist can be used as a pharmaceutically acceptable salt, which includes inorganic salts (metal salts, non-metallic salts), organic salts (acidic or basic organic matter), and complex salts (compounds having both acid radicals and bases).

[0014] The PPARα / δ dual agonist includes dosage forms acceptable in medicine, pharmacy, health products, and food, as well as compound dosage forms containing the compound, including injection dosage forms, oral dosage forms, and external dosage forms.

[0015] Furthermore, the injectable dosage forms include injection solutions, freeze-dried powder injections, powder injections, injectable microspheres, liposome injections, solutions, emulsions, suspensions, injectable nanoformulations, and solvent infusions compatible therewith; the oral dosage forms include immediate-release tablets, sustained-release tablets, immediate-release capsules, sustained-release capsules, granules, powders, granules, micropills, microspheres, effervescents, pastes, capsules, rapid-release preparations, mixtures, oral liquid dosage forms, and oral nanoformulations; the external-use dosage forms include external-use sprays, internal-use sprays, inhalants, tinctures, effervescents, suppositories, patches, ointments, gels, plasters, films, pastes, drops, liniments, and external-use nanoformulations.

[0016] The pharmaceutical composition for preventing or treating polycystic kidney disease (PKD) of the present invention comprises a PPARα / δ dual agonist or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient and carrier composition.

[0017] The polycystic kidney disease includes autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

[0018] The dosage form of the composition of the compound, excipients and carrier is capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

[0019] Based on the different gene regulatory effects and human tissue distribution of the three subtypes of PPARs, the present invention is the first to use compounds that simultaneously and selectively activate both PPAR-α and δ(β) receptors, such as 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid, 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid, and 2-[2,6-dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methylpropanoic acid, to conduct efficacy tests on PKD model animals. These compounds have very good effects on PKD, strongly suggesting that these compounds have broad prospects for the treatment of PKD.

[0020] Among them, the compound includes 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (DA002S), and the chemical structure is shown below:

[0021] Among them, 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (DA002S / V1) has the following chemical structure:

[0022] Among them, 2-[2,6-dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methylpropanoic acid (GFT505) has the following chemical structure:

[0023] In the present invention, Pkd1 flox / flox Homozygous kidney-specific Pkd1 knockout mice, obtained by crossbreeding mice with Ksp-Cre mice and then self-fertilizing, are currently one of the internationally recognized classic animal models of polycystic kidney disease, allowing for rapid characterization of drug efficacy and toxicity in PKD. Using tolvaptan (TVP) as a positive control group, the results showed that DA002S and DA002SV1 exhibited greater activity.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0025] The present invention provides for the first time the use of a PPARα / δ dual agonist in the treatment of polycystic kidney disease, offering a novel option for the treatment of PKD and promising therapeutic prospects. In vivo experiments demonstrate that, compared with a model control group, mice treated with TVP, DA002S, DA002S / V1, and GFT505 had smaller kidney volumes, indicating a better therapeutic effect. Analysis of the kidney weight index of mice revealed a decrease in the kidney weight index of mice treated with TVP, DA002S, DA002S / V1, and GFT505 compared with the control group. Furthermore, all three compounds, DA002S, DA002S / V1, and GFT505, exhibited therapeutic effects similar to those of the positive drug, TVP. H&E staining of renal tissue sections revealed a significant decrease in the number and area of ​​vesicles in mice treated with TVP, DA002S, DA002S / V1, and GFT505 compared with the control group. These results indicate that DA002S, DA002S / V1, and GFT505 have a better therapeutic effect.

[0026] In an acute ADPKD mouse model, compared with the control group, mice treated with TVP (1 mg / kg), DA002S (1 mg / kg), DA002S / V1 (0.1 mg / kg), and GFT505 (10 mg / kg) showed reduced kidney volume and a significant decrease in kidney mass index. Furthermore, the renal cysticity index (cyst area) of the mice significantly decreased, indicating that cyst development was inhibited. The in vivo efficacy of DA002S was superior to that of an equivalent dose of tolvaptan, and the efficacy of DA002S / V1 at a lower dose significantly exceeded that of a high-dose tolvaptan. In summary, DA002S, DA002S / V1, and GFT505 demonstrated inhibitory effects on the progression of polycystic kidney disease (PCK) and improved renal function, demonstrating promising in vivo efficacy for ADPKD. The compounds of this invention also exhibit promising therapeutic effects for ARPKD.

[0027] Therefore, the present invention discovered for the first time that PPARα / δ dual agonists or pharmaceutically acceptable salts thereof can significantly improve the polycystic kidney phenotype in acute ADPKD / ARPKD model mice, and thus can be used to prepare drugs for preventing or treating polycystic kidney disease (PKD). BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 shows kidney images of representative animals dissected at the end of drug administration in wild-type WT mice, ADPKD model control vehicle group, TVP 1 mg / kg, DA002S 1 mg / kg, DA002S / V1 0.1 mg / kg, and GFT505 10 mg / kg administration groups;

[0029] Figure 2 shows a bar graph of the renal index (bilateral kidney mass / mouse body weight) of mice in the ADPKD model control vehicle group, TVP 1 mg / kg, DA002S 1 mg / kg, DA002S / V1 0.1 mg / kg, and GFT505 10 mg / kg groups. Mean ± SD, n = 6. ***P < 0.001, **P < 0.01 compared with the vehicle group.

[0030] Figure 3 shows H&E staining of kidney sections of mice in the ADPKD model control Vehicle group, TVP 1 mg / kg, DA002S 1 mg / kg, DA002S / V1 0.1 mg / kg, and GFT505 10 mg / kg treatment groups. DETAILED DESCRIPTION

[0031] The following examples are provided to illustrate the present invention in detail. The following examples are provided to better illustrate the present invention and are not intended to limit the scope of the present invention.

[0032] In the embodiments, 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid, 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid, and 2-[2,6-dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methylpropanoic acid were synthesized according to the methods in the prior art.

[0033] Pkd1 flox / flox Homozygous kidney-specific Pkd1 knockout mice were obtained by self-crossing mice with Ksp-Cre mice. These mice develop renal cysts during the embryonic stage and rapidly progress to renal failure. This acute ADPKD mouse model was constructed using the method described in Hum Mol Genet. 2008 Jun 1; 17(11): 1505-16.

[0034] Example 1

[0035] Pkd1 flox / flox Homozygous kidney-specific Pkd1 knockout mice were obtained by crossing mice with Ksp-Cre mice and then self-crossing. These mice develop renal cysts during the embryonic stage and rapidly progress to renal failure, serving as a mouse model of acute ADPKD.

[0036] The acute ADPKD mouse model drug administration experiment was conducted with 5 groups, namely, model control group, 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl) The mice were treated with 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (DA002S, 1 mg / kg), 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (DA002S / V1, 0.1 mg / kg), and 2-[2,6-dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methylpropanoic acid (GFT505, 10 mg / kg), as well as a positive drug control group, tolvaptan (TVP, 1 mg / kg), with 6 animals in each group. Mice were administered subcutaneously starting on day 6 of life and given once a day for 7 consecutive days. On day 12 of the experiment, the mice's kidney weight index (bilateral kidney weight / mouse body weight) and kidney tissue morphology (H&E staining of tissue sections) were analyzed and compared to evaluate the improvement effects of DA002S, DA002S / V1, and GFT505 on the polycystic kidney phenotype in acute ADPKD model mice. The results are shown in Figures 1 to 3.

[0037] The results showed that compared with the model control group, the kidney volume of mice treated with TVP, DA002S, DA002S / V1 and GFT505 was smaller, indicating a better treatment effect (Figure 1). In particular, the kidney volume of mice treated with low-dose DA002S / V1 was the smallest, and the effect was more significant, significantly exceeding the high-dose positive control drug TVP. After analyzing the kidney weight index of mice, it was found that compared with the control group, the kidney weight index of mice treated with TVP, DA002S, DA002S / V1 and GFT505 was reduced ( ** P<0.01, *** P < 0.001 VS Vehicle group) (Figure 2). At the same time, the three compounds DA002S, DA002S / V1, and GFT505 all showed therapeutic effects similar to the positive drug TVP. H&E staining of kidney tissue sections showed that compared with the control group, the number and area of ​​vesicles in mice treated with TVP, DA002S, DA002S / V1, and GFT505 were significantly reduced (Figure 3). Among them, the number and area of ​​vesicles in mice treated with low-dose DA002S / V1 were the smallest, and the effect was more significant, significantly exceeding that of the high-dose positive control drug TVP. These results indicate that DA002S, DA002S / V1, and GFT505 have good therapeutic effects on ADPKD.

[0038] In summary, in an acute ADPKD mouse model, compared with the model control group, mice treated with TVP (1 mg / kg), DA002S (1 mg / kg), DA002S / V1 (0.1 mg / kg), and GFT505 (10 mg / kg) showed reduced kidney volume and a significant decrease in kidney weight index. Furthermore, the renal cysticity index (cyst area) of the mice was significantly reduced, indicating that cyst development was inhibited. The in vivo efficacy of DA002S was superior to that of an equivalent dose of tolvaptan, and the efficacy of DA002S / V1 at a lower dose significantly exceeded that of a high-dose tolvaptan. In summary, DA002S, DA002S / V1, and GFT505 demonstrated inhibitory effects on the progression of polycystic kidney disease (PKD) and improved renal function, demonstrating promising in vivo efficacy in ADPKD. Other compounds of the present invention also exhibited similar effects and demonstrated promising therapeutic effects in the ARPKD model. These compounds can be used to prepare drugs for the prevention or treatment of polycystic kidney disease (PKD).

Claims

1. Use of a PPARα / δ dual agonist or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating polycystic kidney disease (PKD).

2. The use according to claim 1, characterized in that The polycystic kidney disease includes autosomal dominant (adult-type) polycystic kidney disease (ADPKD) and autosomal recessive (infantile-type) polycystic kidney disease (ARPKD).

3. The use according to claim 1, characterized in that The PPARα / δ dual agonist includes any one of the compounds protected in the following documents or patents: (1) European Journal of Pharmacology 882(2020)173300; (2) Bioorganic Chemistry 99(2020)103803; (3) European Journal of Medicinal Chemistry 218(2021)113388; (4) Bioorganic&Medicinal Chemistry 24(2016)5455–5461; (5) Bioorganic&Medicinal Chemistry Letters 16(2006)554–558; (6) Chemistry&Biology December 1997.4:909-918, ACS Med.Chem.Lett.2019,10,1068-1073;(7)PCT patent PCTCN2022072221);(8)PCT patent PCTCN2022141359;(9)PCT patent PCTCN2024072800.

4. The use according to claim 1, characterized in that The PPARα / δ dual agonist is selected from any one of the following compounds:

5. The use according to claim 1, characterized in that The PPARα / δ dual agonist includes any one of 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid, 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid, and 2-[2,6-dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methylpropanoic acid.

6. The use according to claim 1, characterized in that The PPARα / δ dual agonist can be used as a pharmaceutically acceptable salt, which includes an inorganic salt, an organic salt or a composite salt.

7. The use according to claim 1, characterized in that The PPARα / δ dual agonist includes dosage forms acceptable in medicine, pharmacy, health products, and food, as well as compound dosage forms containing the compound, including injection dosage forms, oral dosage forms, and external dosage forms.

8. The use according to claim 6, characterized in that The injectable dosage forms include injection solutions, freeze-dried powder injections, powder injections, injectable microspheres, liposome injections, solutions, emulsions, suspensions, injectable nanoformulations, and solvent infusions compatible therewith; the oral dosage forms include immediate-release tablets, sustained-release tablets, immediate-release capsules, sustained-release capsules, granules, powders, granules, micropills, microspheres, effervescents, pastes, capsules, rapid-release preparations, mixtures, oral liquid dosage forms, and oral nanoformulations; the external-use dosage forms include external-use sprays, internal-use sprays, inhalants, tinctures, effervescents, suppositories, patches, ointments, gels, plasters, films, pastes, drops, liniments, and external-use nanoformulations.

9. A pharmaceutical composition for preventing or treating polycystic kidney disease (PKD), comprising a PPARα / δ dual agonist or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable excipient, and a drug delivery system.

10. The pharmaceutical composition according to claim 9, characterized in that The polycystic kidney disease includes autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

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