Combined medicine for preventing and / or treating obesity

Abstract

The invention belongs to the field of chemical medicines, and particularly relates to a combined medicine for preventing and / or treating obesity. The combined medicine disclosed by the invention is a combined medicine of a THR-beta agonist and a GLP-1 receptor agonist. The combined medicine disclosed by the invention can achieve a synergistic effect, can reduce body weight by increasing fat metabolism, reducing fat content, controlling appetite, delaying gastric emptying, increasing satiety and the like, can be used as an effective strategy for solving the obesity problem, and has a wide application prospect.

Description

Technical Field

[0001] The invention belongs to the field of chemical medicine, and in particular relates to a combined medicine for preventing and / or treating obesity. Background Art

[0002] Obesity refers to excessive total body fat and / or increased local fat content and abnormal distribution. It is a chronic metabolic disease caused by the combined effects of genetic and environmental factors. The World Health Organization defines body mass index (BMI) as 25.0 to 29.9 kg / m -2 It is considered overweight when ≥30kg·m –2 Obesity. my country's obesity expert group recommends a BMI of 24.0 to 27.9 kg / m –2 It is considered overweight when ≥28kg·m –2 Obesity. Obesity can cause a series of health problems, such as increasing the risk of various chronic diseases such as hypertension, diabetes, cardiovascular and cerebrovascular diseases and tumors, and can also lead to social and psychological problems. It has become one of the major public health problems in my country. Therefore, early intervention in obesity is of great significance for preventing and controlling the occurrence and development of its complications.

[0003] The lipid-lowering and weight-reducing effects of thyroid hormones and thyroid hormone analogs have always been a hot topic of research. Animal studies in recent years have found that thyroid hormone receptor β (THRβ) agonists such as KB-141 and GC-1 can reduce body weight by increasing tissue oxygen consumption, reducing fat content. In addition, these preparations can also reduce the levels of low-density lipoprotein-cholesterol, lipoprotein a, and triglycerides, effectively reducing the risk of atherosclerosis. At the same time, these drugs can speed up metabolism without increasing food intake, nor cause adverse cardiovascular reactions such as increased heart rate. It can be seen that THRβ agonists are expected to become potential new weight-loss and lipid-lowering drugs.

[0004] Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone with multiple effects. GLP-1 receptor agonist (GLP-1RA), on the one hand, can intelligently respond to high blood sugar, promote increased insulin secretion, and inhibit the release of glucagon. When blood sugar rises, it helps the body to more effectively regulate blood sugar levels, and is used to treat type 2 diabetes mellitus (T2DM); on the other hand, it acts on the central and peripheral nervous systems to control appetite and delay gastric emptying, thereby increasing satiety, reducing food intake, and achieving weight loss. Liraglutide and semaglutide injection are GLP-1RAs preparations, which were approved by the FDA for the treatment of obesity in 2014 and 2021, respectively, with excellent weight loss effects.

[0005] Although current weight loss drugs have achieved certain therapeutic effects, they still have serious adverse reactions, resulting in poor results. Therefore, it is urgent to find a new drug for the treatment of obesity to improve the effectiveness, safety and compliance of the drug and provide more treatment options for overweight and obese people. Summary of the invention

[0006] In view of the defects in the prior art, the present invention provides a combined drug for preventing and / or treating obesity, which has higher safety and better efficacy and can be used as an effective strategy to solve the problem of obesity.

[0007] A combined drug for preventing and / or treating obesity, wherein the combined drug is a THR-β agonist and a GLP-1 receptor agonist.

[0008] Preferably, the combined drug is a THR-β agonist and a GLP-1 receptor agonist, which are administered separately or simultaneously.

[0009] Preferably, the weight ratio of the THR-β agonist to the GLP-1 receptor agonist is (15-150):(3-400) or (10-200):(0.04-100).

[0010] Preferably, the THR-β agonist is selected from at least one of small molecule chemical drugs and chemical drugs;

[0011] The small molecule chemical drugs are resmetirox (MGL-3196), thyroxine, liothyronine sodium, tirarax, ALG-055009, MB-07811, ABX-002, ASC-41, HSK-31679, TERN-501, ASC-43F, CS-060380, Kylo-0603, ECC-4703, VK-0214, CS-060304, HPG-7233, KH-629, 3,5-Dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic At least one of acid, Sobetirome, CVI-301, KY-41111, BCT-305, BCT-306, CVI-NP2, ABX-003, SKL-12846, KB-141, 3,5-Dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid(11a), LL-341070, SKL-13784, MGL-3745, Eprotirome, ASC45F, KTA-439, ZYT-1, ASC-41, CS-70001, and CNPT-101101;

[0012] And / or, the chemical drug is at least one of CVI-2742, Cyta-001, and KTA-574.

[0013] Preferably, the THR-β agonist is as shown in Formula I:

[0014]

[0015] Wherein X and Y are selected from halogen.

[0016] Preferably, the structural formula of Formula I is as follows:

[0017]

[0018] Preferably, the GLP-1 receptor agonist is selected from at least one of polypeptide drugs, small molecule chemical drugs, fusion protein drugs, biosimilar drugs, hormone drugs, chemical drugs, biological drugs, recombinant protein drugs, adeno-associated virus gene therapy drugs, antibody fusion protein drugs, gene therapy drugs, conjugated drugs, mRNA drugs, monoclonal antibody drugs, bispecific antibody drugs, mesenchymal stem cell therapy drugs, and protein drugs;

[0019] The polypeptide drugs are semaglutide, polyethylene glycol loxenatide, dulaglutide, levofloxacin, exenatide, QLG 2065, liraglutide, pegylated exenatide, efpeglenatide, NLY-01, albiglutide, telpotide, mastitutide, retaglutide, froniglutide, Gln28Exenatide, ANY002, utreglutide, NNC0113-6856, pegsebrenatide, glucagon-like peptide-1, INV-610, GUB021794, SHX-022, HDNO-1765, IP118, Q9P, BL OPUS II, DWRX-5003, ITCA-884, NPM 139. Semaglutide-IXB-401, HSP-005, Cbi-Ex4, SPN009, HSP-012C, BMS-686117, MET-0 6. NPM-159, MEDI-7219, CJC-1131, SDE-124, Dance-601, AS, AER-601, TH-0318, tapglutide, CS 872, Curaglutide, NN-9927, ITCA-880, Org-249305, HTI-2088, AC-3174, CW-7213, LP-9, CGEN-G11, FT228 ZY-D1 CRY-001 OP-286CR CAM-2036 AC2592 NN-9926 Val8-GLP-1 BK-0086 NN- 9925, P-5, ZYOG-1, SHR-2042, SXGLP1, PG-004, gSaxenda, Survodutide, HRS-9531, BGM-0 504, DD-01, Cotadutide, VK-2735, RAY1225, CT-388, Efinopegdutide, TB-001, Dapiglut ide, pemvidutide, olatorepatide, CT-868, PB-718, HDM-1005, HZ-010, NN-9490, UBT-25 1, DA-1726, LY-3493269, NN9542, Bamadutide, DR10627, ZP-2929, LY-3537031, THDBH1 Tirzepatide, BCGluExe, Pramlintide, THDBH121, MWN109, SPN-007, PB-2301, AC170222 OXM-101, HLB1-006, G-49, LM06, GEP44, MK-1462, AGM-217, PP18, RG-7697, CIN-210, HTL -023 ZP-GG-72 GEP12 PB-2309 LDM-3 HISHS-2001 OXM Pegapamodutide MK-8521 NN 9709 OAP-189 RO-6807952 SAR-438335 Oxyntomodulin MOD-6030 DA3-CH MEDI-416 6 CIN-209 SAR-441255 TKS-1225 DA-CH5 GUB06-046 RNTP-001A Recombinant exenatide-4, CagriSema, NNC0519-0130, ZT002, Diapin, DD-15, PF-1807, HLB1-015, DD-14, CMZ-371, DD02S, DR-10601, BZ-043B. NN-9928, NB-1001, VRS-859, ROSE-010, PSA-oxyntomodulin, NN- 9223. Glymera. PF-4856883. 4P-004. GB-7001.

[0020] And / or, the small molecule chemical drug is HRS-7535, Orforglipron, NA-931, HDM1002, VCT220, Dagliron, MDR-001, SAL-0112, ECC-5004, Aleniglipron, AZD-9550, HZ-012, Lotiglipron, BI-3006337, ID-110521156, PF-06954522, XW-014, THDBH110, TERN-601, HMS 5678, SCO-094, CT-996, ASC-30, KP-405, TY-751, TY705, MLX-7006, NN1177, PGN-OB2, AX18, TT-OAD2, MLX 7000, LuCI, GT-01123, GSBR-2nd Gen, RGT-274, ZP4165, BEBT-808, TTP-273, DD202-114, YGX1, WB4-24, YH-40863, CYRS-MD02, RV-003, MRANK111, Lotiglipron At least one of tromethamine, LSN-3318839, IGC-1A, AZD-0186, AST-6055, MK-5823, AB-301, HNC1031, Boc-5, FP-005, ID-11052, EP45, KR-69318, RDX-98940, RP-9056, K-579, TTP-054, JNJ-54728518, NNC-92041706, AGM-212, AZM-134, HD-7671, BHM-089, and LXM.2;

[0021] And / or, the fusion protein drug is Supaglutide, SAL-015, JY-09, TG103, Efocipegtrutide, HEC-88473, MWN-101, DR10624, AMG-133, DR10628, SHR-1816, AP-026, Byetalog, GW002, YH-25724, MWN105, MWN-103, dulaglutide, GLP1-ELP-FGF21, TB-59-2, MWN115, rHSA-GLP-1, OGB-21502, GLP-1-Fc-FGF21 At least one of D1, OGB-21501, CVX-478, AMPE4L, GSK-2374697, DR10625, CNTO-3649, DR10619, E2HSA, CNTO-736, BA-5101, and RBS-006;

[0022] and / or, the biosimilar drug is at least one of Bellarine, Lirafit, Tonbol, Lilupin, Jikeqin, BA-5101, CA-505, HDG-1901, TQF-3510, 4P-004, PG-001, MAR-531, DS-004, DS-006, PG-004, GB-7001, DS-012, RBS-006, and RD-12014;

[0023] And / or, the hormone drug is at least one of NovoElix, Saiyining, HR-17031, SL-209, Icosema, Amycretin, GLP-06, ACT-1003, BL OPUS IV, OXM-001, MBX-4291, GLP-1CCM, JNASE-7001, and BEM-041;

[0024] and / or, the chemical drug is at least one of APH01727, DD-03, OXM-104, HSP-016, HISHS-3001, XFL6, D-314, CY-5, DA-JC1, and DA-JC4;

[0025] and / or, the biopharmaceutical is at least one of Bofanglutide, LBT-6030, VTC-G15, AM-1118, ME001, SN-006, SYNT-101, ATBB-22, XW-015, PF-4603629, NN-9277, BEM-012, HYBR-011, LY-548806, and ZP-3022;

[0026] and / or, the recombinant protein drug is at least one of enoglutide, ZT-003, ZT-007, and HTB-C041;

[0027] and / or, the adeno-associated virus gene therapy drug is at least one of AAV-Ex-4, KT-A522, and rAd-GLP-1;

[0028] And / or, the antibody fusion protein drug is at least one of ZX2010 and ZX2021;

[0029] and / or, the gene therapy drug is at least one of Y002 and RMD-1202;

[0030] And / or, the conjugated drug is at least one of SNC-001 and GLP-1-MK-801;

[0031] and / or, the mRNA drug is HFG1;

[0032] and / or, the monoclonal antibody drug is glutarizumab;

[0033] and / or, the bispecific antibody drug is GMA-106;

[0034] And / or, the mesenchymal stem cell therapy drug is a fat stem cell injection solution with high expression of human GLP-1 and FGF21 dual factors;

[0035] And / or, the protein drug is ZT-005.

[0036] Preferably, when the THR-β agonist and / or GLP-1 receptor agonist is selected from small molecule chemical drugs, the small molecule chemical drugs are deuterated compounds thereof.

[0037] Preferably, the THR-β agonist is selected from Compound 2, and the GLP-1 receptor agonist is selected from at least one of semaglutide, telpotide, and orforglipron; the structural formula of Compound 2 is

[0038] The present invention also provides use of the above-mentioned combined drug in preparing a drug for preventing and / or treating obesity.

[0039] The present invention also provides a pharmaceutical composition for preventing and / or treating obesity, which is prepared by using a THR-β agonist and a GLP-1 receptor agonist as active ingredients and adding pharmaceutically acceptable excipients or auxiliary ingredients; the weight ratio of the THR-β agonist to the GLP-1 receptor agonist is (15-150):(3-400) or (10-200):(0.04-100).

[0040] Preferably, the THR-β agonist is selected from at least one of small molecule chemical drugs and chemical drugs;

[0041] The small molecule chemical drugs are resmetirox, thyroxine, liothyronine sodium, tirlatrex, ALG-055009, MB-07811, ABX-002, ASC-41, HSK-31679, TERN-501, ASC-43F, CS-060380, Kylo-0603, ECC-4703, VK-0214, CS-060304, HPG-7233, KH-629, 3,5-Dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic At least one of acid, Sobetirome, CVI-301, KY-41111, BCT-305, BCT-306, CVI-NP2, ABX-003, SKL-12846, KB-141, 3,5-Dibromo-4-[(4-hydroxy-3-isopropylphenox y)phenyl]acetic acid (11a), LL-341070, SKL-13784, MGL-3745, Eprotirome, ASC45F, KTA-439, ZYT-1, ASC-41, CS-70001, and CNPT-101101;

[0042] And / or, the chemical drug is at least one of CVI-2742, Cyta-001, and KTA-574.

[0043] Preferably, the THR-β agonist is as shown in Formula I:

[0044]

[0045] Wherein X and Y are selected from halogen.

[0046] Preferably, the structural formula of Formula I is as follows:

[0047]

[0048] Preferably, the GLP-1 receptor agonist is selected from at least one of polypeptide drugs, small molecule chemical drugs, fusion protein drugs, biosimilar drugs, hormone drugs, chemical drugs, biological drugs, recombinant protein drugs, adeno-associated virus gene therapy drugs, antibody fusion protein drugs, gene therapy drugs, conjugated drugs, mRNA drugs, monoclonal antibody drugs, bispecific antibody drugs, mesenchymal stem cell therapy drugs, and protein drugs;

[0049] The polypeptide drugs are semaglutide, polyethylene glycol loxenatide, dulaglutide, levofloxacin, exenatide, QLG 2065, liraglutide, pegylated exenatide, efpeglenatide, NLY-01, albiglutide, telpotide, mastitutide, retaglutide, froniglutide, Gln28Exenatide, ANY002, utreglutide, NNC0113-6856, pegsebrenatide, glucagon-like peptide-1, INV-610, GUB021794, SHX-022, HDNO-1765, IP118, Q9P, BL OPUS II, DWRX-5003, ITCA-884, NPM 139. Semaglutide-IXB-401, HSP-005, Cbi-Ex4, SPN009, HSP-012C, BMS-686117, MET-0 6. NPM-159, MEDI-7219, CJC-1131, SDE-124, Dance-601, AS, AER-601, TH-0318, tapglutide, CS 872, Curaglutide, NN-9927, ITCA-880, Org-249305, HTI-2088, AC-3174, CW-7213, LP-9, CGEN-G11, FT228 ZY-D1 CRY-001 OP-286CR CAM-2036 AC2592 NN-9926 Val8-GLP-1 BK-0086 NN- 9925, P-5, ZYOG-1, SHR-2042, SXGLP1, PG-004, gSaxenda, Survodutide, HRS-9531, BGM-0 504, DD-01, Cotadutide, VK-2735, RAY1225, CT-388, Efinopegdutide, TB-001, Dapiglut ide, pemvidutide, olatorepatide, CT-868, PB-718, HDM-1005, HZ-010, NN-9490, UBT-25 1, DA-1726, LY-3493269, NN9542, Bamadutide, DR10627, ZP-2929, LY-3537031, THDBH1 Tirzepatide, BCGluExe, Pramlintide, THDBH121, MWN109, SPN-007, PB-2301, AC170222 OXM-101, HLB1-006, G-49, LM06, GEP44, MK-1462, AGM-217, PP18, RG-7697, CIN-210, HTL -023 ZP-GG-72 GEP12 PB-2309 LDM-3 HISHS-2001 OXM Pegapamodutide MK-8521 NN 9709 OAP-189 RO-6807952 SAR-438335 Oxyntomodulin MOD-6030 DA3-CH MEDI-416 6 CIN-209 SAR-441255 TKS-1225 DA-CH5 GUB06-046 RNTP-001A Recombinant exenatide-4, CagriSema, NNC0519-0130, ZT002, Diapin, DD-15, PF-1807, HLB1-015, DD-14, CMZ-371, DD02S, DR-10601, BZ-043B. NN-9928, NB-1001, VRS-859, ROSE-010, PSA-oxyntomodulin, NN- 9223. Glymera. PF-4856883. 4P-004. GB-7001.

[0050] And / or, the small molecule chemical drug is HRS-7535, Orforglipron, NA-931, HDM1002, VCT220, Dagliron, MDR-001, SAL-0112, ECC-5004, Aleniglipron, AZD-9550, HZ-012, Lotiglipron, BI-3006337, ID-110521156, PF-06954522, XW-014, THDBH110, TERN-601, HMS 5678, SCO-094, CT-996, ASC-30, KP-405, TY-751, TY705, MLX-7006, NN1177, PGN-OB2, AX18, TT-OAD2, MLX 7000, LuCI, GT-01123, GSBR-2nd Gen, RGT-274, ZP4165, BEBT-808, TTP-273, DD202-114, YGX1, WB4-24, YH-40863, CYRS-MD02, RV-003, MRANK111, Lotiglipron At least one of tromethamine, LSN-3318839, IGC-1A, AZD-0186, AST-6055, MK-5823, AB-301, HNC1031, Boc-5, FP-005, ID-11052, EP45, KR-69318, RDX-98940, RP-9056, K-579, TTP-054, JNJ-54728518, NNC-92041706, AGM-212, AZM-134, HD-7671, BHM-089, and LXM.2;

[0051] And / or, the fusion protein drug is Supaglutide, SAL-015, JY-09, TG103, Efocipegtrutide, HEC-88473, MWN-101, DR10624, AMG-133, DR10628, SHR-1816, AP-026, Byetalog, GW002, YH-25724, MWN105, MWN-103, dulaglutide, GLP1-ELP-FGF21, TB-59-2, MWN115, rHSA-GLP-1, OGB-21502, GLP-1-Fc-FGF21 At least one of D1, OGB-21501, CVX-478, AMPE4L, GSK-2374697, DR10625, CNTO-3649, DR10619, E2HSA, CNTO-736, BA-5101, and RBS-006;

[0052] and / or, the biosimilar drug is at least one of Bellarine, Lirafit, Tonbol, Lilupin, Jikeqin, BA-5101, CA-505, HDG-1901, TQF-3510, 4P-004, PG-001, MAR-531, DS-004, DS-006, PG-004, GB-7001, DS-012, RBS-006, and RD-12014;

[0053] And / or, the hormone drug is at least one of NovoElix, Saiyining, HR-17031, SL-209, Icosema, Amycretin, GLP-06, ACT-1003, BL OPUS IV, OXM-001, MBX-4291, GLP-1CCM, JNASE-7001, and BEM-041;

[0054] and / or, the chemical drug is at least one of APH01727, DD-03, OXM-104, HSP-016, HISHS-3001, XFL6, D-314, CY-5, DA-JC1, and DA-JC4;

[0055] and / or, the biopharmaceutical is at least one of Bofanglutide, LBT-6030, VTC-G15, AM-1118, ME001, SN-006, SYNT-101, ATBB-22, XW-015, PF-4603629, NN-9277, BEM-012, HYBR-011, LY-548806, and ZP-3022;

[0056] and / or, the recombinant protein drug is at least one of enoglutide, ZT-003, ZT-007, and HTB-C041;

[0057] and / or, the adeno-associated virus gene therapy drug is at least one of AAV-Ex-4, KT-A522, and rAd-GLP-1;

[0058] And / or, the antibody fusion protein drug is at least one of ZX2010 and ZX2021;

[0059] and / or, the gene therapy drug is at least one of Y002 and RMD-1202;

[0060] And / or, the conjugated drug is at least one of SNC-001 and GLP-1-MK-801;

[0061] and / or, the mRNA drug is HFG1;

[0062] and / or, the monoclonal antibody drug is glutarizumab;

[0063] and / or, the bispecific antibody drug is GMA-106;

[0064] And / or, the mesenchymal stem cell therapy drug is a fat stem cell injection solution with high expression of human GLP-1 and FGF21 dual factors;

[0065] And / or, the protein drug is ZT-005.

[0066] Preferably, the THR-β agonist is selected from Compound 2, and the GLP-1 receptor agonist is selected from at least one of semaglutide, telpotide, and orforglipron; the structural formula of Compound 2 is

[0067] Preferably, when the THR-β agonist and / or GLP-1 receptor agonist is selected from small molecule chemical drugs, the small molecule chemical drugs are deuterated compounds thereof.

[0068] The present invention combines a THR-β agonist with a GLP-1 receptor agonist for the first time, which has a synergistic effect and can significantly reduce fat content without increasing muscle loss, thereby achieving high-quality weight loss. It is used to prevent and / or treat obesity and has broad application prospects.

[0069] Among them, the chemical structural formulas of some compounds of THR-β agonists are shown in Table 1; the chemical structural formulas of some compounds of GLP-1 receptor agonists are shown in Table 2.

[0070] Table 1 Some THR-β agonists and their chemical structures

[0071]

[0072]

[0073]

[0074] Table 2 Some GLP-1 receptor agonists and their chemical structures

[0075]

[0076] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0077] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 Figure 2 shows the changes in body weight of mice during administration of the high-fat diet-induced obesity model.

[0079] Figure 2 The changes in muscle and fat mass of mice were compared before and after administration for 42 days.

[0080] Figure 3 The TG and TC levels in the liver of mice after 42 days of drug administration.

[0081] Figure 4 The blood TG, TC and LDL-c levels of mice were measured after 42 days of drug administration.

[0082] Figure 5 Respiratory Exchange Ratio (RER) is the blood energy consumption of mice after 42 days of drug administration. DETAILED DESCRIPTION

[0083] In the following examples and experimental examples, reagents and raw materials not specifically described are all commercially available products.

[0084] The structural formula of THR-β agonist compound 2 is

[0085] Example 1 Combination drug for treating obesity

[0086] This embodiment provides a combination drug for treating obesity, which is a combination drug comprising 30 mg of Compound 2 and 0.12 mg of semaglutide.

[0087] Example 2 Combination drug for treating obesity

[0088] This embodiment provides a combination drug for treating obesity, which is a combination drug comprising 15 mg of Compound 2 and 400 mg of semaglutide.

[0089] Example 3 Combination drug for treating obesity

[0090] This embodiment provides a combination drug for treating obesity, which is a combination drug comprising 150 mg of Compound 2 and 3 mg of semaglutide.

[0091] Example 4 Combination drug for treating obesity

[0092] This embodiment provides a combination drug for treating obesity, which is a combination drug comprising 200 mg of Compound 2 and 0.04 mg of semaglutide.

[0093] Example 5 Combination drug for treating obesity

[0094] This embodiment provides a combination drug for treating obesity, which is a combination drug comprising 10 mg of Compound 2 and 100 mg of semaglutide.

[0095] The technical solution of the present invention is further illustrated by experiments below.

[0096] Experimental Example 1: Pharmacodynamic effects of THR-β agonist compound 2 combined with GLP-1 receptor agonist semaglutide in an obese mouse model

[0097] 1. Experimental Methods

[0098] Obesity model (DIO) was established by inducing C57BL / 6J mice with 60% high-fat diet, and the in vivo pharmacodynamics of compound 2 combined with semaglutide were evaluated. 60 DIO mice were randomly divided into 6 groups: vehicle group, compound 2 30mg / kg group (Compound 2 30mg / kg group), semaglutide30 nmol / kg group, semaglutide3nmol / kg+Compound 2 30mg / kg group, semaglutide 30nmol / kg+Compound 2 3mg / kg group, semagluti de30 nmol / kg+Compound 2 30mg / kg group. The structural formula of compound 2 is

[0099]

[0100] Ten C57BL / 6J mice fed with a normal diet served as the negative control group (Chowvehicle group). Semaglutide and Compound 2 were administered subcutaneously and intragastrically once daily for 6 consecutive weeks. During the experiment, the body weight, body fat ratio, liver TC and TG content, blood TG, TC and LDL-C content, and energy consumption (Respiratory Exchange Ratio (RER)) of the mice were monitored.

[0101] 2. Experimental Results

[0102] The weight changes of mice during the experiment were as follows Figure 1As shown: Compared with the Chowvehicle group, the vehicle group of DIO mice had increased body weight. The Compound 2 30mg / kg group had decreased body weight compared with the vehicle group, and the semaglutide 30nmol / kg group had significantly decreased body weight compared with the vehicle group; the semaglutide 3nmol / kg+Compound 2 30mg / kg group and the semaglutide 30nmol / kg+Compound 23mg / kg group had more significant weight loss compared with the Semaglutide 30nmol / kg group; the semaglutide 30nmol / kg+Compound 2 30mg / kg group had the most significant weight loss compared with the Semaglutide 30nmol / kg group, and it was dose-dependent; the results showed that the combination of Compound 2 and semaglutide can produce a synergistic effect in the treatment of obesity.

[0103] The results of mouse body fat ratio are as follows Figure 2 As shown, the baseline body fat ratio 2 days before administration showed that the body weight and fat mass of the DIO model group were higher than those of mice fed a normal diet, and the muscle content of each group was similar. At the end of 42 days of administration, the semaglutide 30 nmol / kg group reduced 1.7g of muscle mass, and the combined drug groups did not significantly aggravate muscle loss; on the other hand, the Compound 2 30mg / kg group reduced 2.5g of fat mass, the semaglutide 30 nmol / kg group reduced 6.2g of fat mass, the semaglutide 3nmol / kg + Compound 2 30mg / kg group reduced 12.8g of fat mass, the semaglutide 30nmol / kg + Compound 2 3mg / kg group reduced 12.3g of fat mass; the semaglutide 30nmol / kg + Compound 2 30mg / kg group reduced 15.0g of fat mass. The results show that the combination of Compound 2 and semaglutide can significantly reduce fat content without aggravating muscle loss, and the effect is significantly stronger than the efficacy of either component alone.

[0104] Mouse liver biochemical results Figure 3As shown, at the end of 42 days of administration, the TG and TC levels of each administration group were significantly decreased compared with the Vehicle group (P<0.0001). Compared with the semaglutide 30nmol / kg single-drug administration group, the TG and TC of the Compound 2 30mg / kg group and each combination drug group were further significantly decreased, among which the TC content of the semaglutide 3nmol / kg + Compound 2 30mg / kg group decreased most significantly, and the TG content of the semaglutide 30nmol / kg + Compound 2 3mg / kg group decreased most significantly. The results show that the combination drug can significantly reduce the TG and TC content of mouse liver.

[0105] Mouse blood biochemical results Figure 4 As shown, at the end of 42 days of administration, the TG, TC, and LDL-c levels of each administration group were significantly decreased compared with the Vehicle group. Compared with the semaglutide 30nmol / kg single-drug administration group, the TG, TC, and LDL-c levels of the Compound 2 30mg / kg group and each combination drug group were further significantly decreased. Among them, the TG, TC, and LDL-c levels of the semaglutide 3nmol / kg + Compound 2 30mg / kg group decreased most significantly. The results show that the combination drug can significantly reduce the blood TG, TC, and LDL-c levels of mice.

[0106] The results of mouse energy expenditure were as follows Figure 5 As shown, at the end of 42 days of administration, the Respiratory Exchange Ratio (RER) of the four groups of Vehicle, semaglutide 30nmol / kg, Compound 2 30mg / kg, and semaglutide 30nmol / kg combined with Compound 2 30mg / kg was evaluated. The results showed that the combined drug group could increase energy expenditure, and the effect was significantly stronger than the efficacy of any component used alone, with a significant synergistic effect.

[0107] The combination of Compound 2 and telportide has a similar synergistic effect on weight loss. The combination of Compound 2 and Orforglipron also has a similar synergistic effect on weight loss.

[0108] In summary, the combined use of THR-β agonists represented by compound 2 and GLP-1 agonists represented by semaglutide can significantly reduce the weight of obese animals, significantly reduce TG, TC, and LDL-c content, increase energy consumption, achieve a higher muscle / fat ratio, and achieve high-quality fat reduction effects, with a synergistic effect. Therefore, the combination of THR-β agonists and GLP-1 receptor agonists can effectively prevent and / or treat obesity and has broad application prospects.

Claims

1. A combined drug for preventing and / or treating obesity, characterized in that: The combined drug is a THR-β agonist and a GLP-1 receptor agonist.

2. The combined drug according to claim 1, characterized in that: The combined drug is a THR-β agonist and a GLP-1 receptor agonist, which are administered separately or simultaneously.

3. The combined drug according to claim 1, characterized in that: The weight ratio of the THR-β agonist to the GLP-1 receptor agonist is (15-150):(3-400) or (10-200):(0.04-100).

4. The combined drug according to claim 1, characterized in that: The THR-β agonist is selected from at least one of small molecule chemical drugs and chemical drugs; The small molecule chemical drugs are resmetirox, thyroxine, liothyronine sodium, tirarax, ALG-055009, MB-07811, ABX-002, ASC-41, HSK-31679, TERN-501, A SC-43F, CS-060380, Kylo-0603, ECC-4703, VK-0214, CS-060304, HPG-7233, KH-629, 3,5-Dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid, Sobetirome, CVI-301, KY-41111, BCT-305, BCT-306, CVI-NP2, A At least one of BX-003, SKL-12846, KB-141, 3,5-Dibromo-4-[(4-hydroxy-3-isopropylphenox y)phenyl]acetic acid (11a), LL-341070, SKL-13784, MGL-3745, Eprotirome, ASC45F, KTA-439, ZYT-1, ASC-41, CS-70001, and CNPT-101101; And / or, the chemical drug is at least one of CVI-2742, Cyta-001, and KTA-574.

5. The combined drug according to claim 1, characterized in that: The THR-β agonist is shown in Formula I: Wherein X and Y are selected from halogen.

6. The combined drug according to claim 5, characterized in that: The structural formula of Formula I is as follows:

7. The combined drug according to claim 1, characterized in that: The GLP-1 receptor agonist is selected from at least one of polypeptide drugs, small molecule chemical drugs, fusion protein drugs, biosimilar drugs, hormone drugs, chemical drugs, biological drugs, recombinant protein drugs, adeno-associated virus gene therapy drugs, antibody fusion protein drugs, gene therapy drugs, coupled drugs, mRNA drugs, monoclonal antibody drugs, bispecific antibody drugs, mesenchymal stem cell therapy drugs, and protein drugs; The polypeptide drugs are semaglutide, polyethylene glycol loxenatide, dulaglutide, levofloxacin, exenatide, QLG2065, liraglutide, pegylated exenatide, efpeglenatide, NLY-01, albiglutide, telpotide, mastitutide, retaglutide, froniglutide, Gln28Exenatide, ANY002, utreglutide, NNC0113-6856, pegsebrenatide, glucagon-like peptide-1, INV-610, GUB021794, SHX-022, HDNO-1765, IP118, Q9P, BL OPUS II, DWRX-5003, ITCA-884, NPM 139. Semaglutide-IXB-401, HSP-005, Cbi-Ex4, SPN009, HSP-012C, BMS-686117, MET-0 6. NPM-159, MEDI-7219, CJC-1131, SDE-124, Dance-601, AS, AER-601, TH-0318, tapglutide, CS 872, Curaglutide, NN-9927, ITCA-880, Org-249305, HTI-2088, AC-3174, CW-7213, LP-9, CGEN-G11, FT228 ZY-D1 CRY-001 OP-286CR CAM-2036 AC2592 NN-9926 Val8-GLP-1 BK-0086 NN- 9925, P-5, ZYOG-1, SHR-2042, SXGLP1, PG-004, gSaxenda, Survodutide, HRS-9531, BGM-0 504, DD-01, Cotadutide, VK-2735, RAY1225, CT-388, Efinopegdutide, TB-001, Dapiglut ide, pemvidutide, olatorepatide, CT-868, PB-718, HDM-1005, HZ-010, NN-9490, UBT-25 1, DA-1726, LY-3493269, NN9542, Bamadutide, DR10627, ZP-2929, LY-3537031, THDBH1 Tirzepatide, BCGluExe, Pramlintide, THDBH121, MWN109, SPN-007, PB-2301, AC170222 OXM-101, HLB1-006, G-49, LM06, GEP44, MK-1462, AGM-217, PP18, RG-7697, CIN-210, HTL -023 ZP-GG-72 GEP12 PB-2309 LDM-3 HISHS-2001 OXM Pegapamodutide MK-8521 NN 9709 OAP-189 RO-6807952 SAR-438335 Oxyntomodulin MOD-6030 DA3-CH MEDI-416 6 CIN-209 SAR-441255 TKS-1225 DA-CH5 GUB06-046 RNTP-001A Recombinant exenatide-4, CagriSema, NNC0519-0130, ZT002, Diapin, DD-15, PF-1807, HLB1-015, DD-14, CMZ-371, DD02S, DR-10601, BZ-043B. NN-9928, NB-1001, VRS-859, ROSE-010, PSA-oxyntomodulin, NN- 9223. Glymera. PF-4856883. 4P-004. GB-7001. And / or, the small molecule chemical drug is HRS-7535, Orforglipron, NA-931, HDM1002, VCT220, Dagliron, MDR-001, SAL-0112, ECC-5004, Aleniglipron, AZD-9550, HZ-012, Lotiglipron, BI-3006337, ID-110521156, PF-06954522, XW-014, THDBH110, TERN-601, HMS 5678, SCO-094, CT-996, ASC-30, KP-405, TY-751, TY705, MLX-7006, NN1177, PGN-OB2, AX18, TT-OAD2, MLX7000, LuCI, GT-01123, GSBR-2nd Gen, RGT-274, ZP4165, BEBT-808, TTP-273, DD202-114, YGX1, WB4-24, YH-40863, CYRS-MD02, RV-003, MRANK111, Lotiglipron At least one of tromethamine, LSN-3318839, IGC-1A, AZD-0186, AST-6055, MK-5823, AB-301, HNC1031, Boc-5, FP-005, ID-11052, EP45, KR-69318, RDX-98940, RP-9056, K-579, TTP-054, JNJ-54728518, NNC-92041706, AGM-212, AZM-134, HD-7671, BHM-089, and LXM.2; And / or, the fusion protein drug is Supaglutide, SAL-015, JY-09, TG103, Efocipegtrutide, HEC-88473, MWN-101, DR10624, AMG-133, DR10628, SHR-1816, AP-026, Byetalog, GW002, YH-25724, MWN105, MWN-103, dulaglutide, GLP1-ELP-FGF21, TB-59-2, MWN115, rHSA-GLP-1, OGB-21502, GLP-1-Fc-FGF21 At least one of D1, OGB-21501, CVX-478, AMPE4L, GSK-2374697, DR10625, CNTO-3649, DR10619, E2HSA, CNTO-736, BA-5101, and RBS-006; and / or, the biosimilar drug is at least one of Bellarine, Lirafit, Tonbol, Lilupin, Jikeqin, BA-5101, CA-505, HDG-1901, TQF-3510, 4P-004, PG-001, MAR-531, DS-004, DS-006, PG-004, GB-7001, DS-012, RBS-006, and RD-12014; And / or, the hormone drug is at least one of NovoElix, Saiyining, HR-17031, SL-209, Icosema, Amycretin, GLP-06, ACT-1003, BL OPUS IV, OXM-001, MBX-4291, GLP-1CCM, JNASE-7001, and BEM-041; and / or, the chemical drug is at least one of APH01727, DD-03, OXM-104, HSP-016, HISH S-3001, XFL6, D-314, CY-5, DA-JC1, and DA-JC4; and / or, the biopharmaceutical is at least one of Bofanglutide, LBT-6030, VTC-G15, AM-1118, ME001, SN-006, SYNT-101, ATBB-22, XW-015, PF-4603629, NN-9277, BEM-012, HYBR-011, LY-548806, and ZP-3022; and / or, the recombinant protein drug is at least one of enoglutide, ZT-003, ZT-007, and HTB-C041; and / or, the adeno-associated virus gene therapy drug is at least one of AAV-Ex-4, KT-A522, and rAd-GLP-1; And / or, the antibody fusion protein drug is at least one of ZX2010 and ZX2021; and / or, the gene therapy drug is at least one of Y002 and RMD-1202; And / or, the conjugated drug is at least one of SNC-001 and GLP-1-MK-801; and / or, the mRNA drug is HFG1; and / or, the monoclonal antibody drug is glutarizumab; and / or, the bispecific antibody drug is GMA-106; And / or, the mesenchymal stem cell therapy drug is a fat stem cell injection solution with high expression of human GLP-1 and FGF21 dual factors; And / or, the protein drug is ZT-005.

8. The combined drug according to any one of claims 1 to 7, characterized in that: When the THR-β agonist and / or GLP-1 receptor agonist is selected from small molecule chemical drugs, the small molecule chemical drugs are deuterated compounds thereof.

9. The combined drug according to any one of claims 1 to 7, characterized in that: The THR-β agonist is selected from compound 2, and the GLP-1 receptor agonist is selected from at least one of semaglutide, telpotide, and orforglipron; the structural formula of compound 2 is 10. Use of the combined drug according to any one of claims 1 to 9 in the preparation of a drug for preventing and / or treating obesity.

11. A pharmaceutical composition for preventing and / or treating obesity, characterized in that: The invention is prepared by taking THR-β agonist and GLP-1 receptor agonist as active ingredients and adding pharmaceutically acceptable excipients or auxiliary ingredients; the weight ratio of the THR-β agonist and the GLP-1 receptor agonist is (15-150):(3-400) or (10-200):(0.04-100).

12. The pharmaceutical composition according to claim 11, characterized in that: The THR-β agonist is selected from at least one of small molecule chemical drugs and chemical drugs; The small molecule chemical drugs are resmetirox, thyroxine, liothyronine sodium, tirarax, ALG-055009, MB-07811, ABX-002, ASC-41, HSK-31679, TERN-501, A SC-43F, CS-060380, Kylo-0603, ECC-4703, VK-0214, CS-060304, HPG-7233, KH-629, 3,5-Dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid, Sobetirome, CVI-301, KY-41111, BCT-305, BCT-306, CVI-NP2, A At least one of BX-003, SKL-12846, KB-141, 3,5-Dibromo-4-[(4-hydroxy-3-isopropylphenox y)phenyl]acetic acid (11a), LL-341070, SKL-13784, MGL-3745, Eprotirome, ASC45F, KTA-439, ZYT-1, ASC-41, CS-70001, and CNPT-101101; And / or, the chemical drug is at least one of CVI-2742, Cyta-001, and KTA-574.

13. The pharmaceutical composition according to claim 11, characterized in that The THR-β agonist is shown in Formula I: Wherein X and Y are selected from halogen.

14. The pharmaceutical composition according to claim 11, characterized in that The structural formula of Formula I is as follows:

15. The pharmaceutical composition according to claim 11, characterized in that: The GLP-1 receptor agonist is selected from at least one of polypeptide drugs, small molecule chemical drugs, fusion protein drugs, biosimilar drugs, hormone drugs, chemical drugs, biological drugs, recombinant protein drugs, adeno-associated virus gene therapy drugs, antibody fusion protein drugs, gene therapy drugs, coupled drugs, mRNA drugs, monoclonal antibody drugs, bispecific antibody drugs, mesenchymal stem cell therapy drugs, and protein drugs; The polypeptide drugs are semaglutide, polyethylene glycol loxenatide, dulaglutide, levofloxacin, exenatide, QLG2065, liraglutide, pegylated exenatide, efpeglenatide, NLY-01, albiglutide, telpotide, mastitutide, retaglutide, froniglutide, Gln28Exenatide, ANY002, utreglutide, NNC0113-6856, pegsebrenatide, glucagon-like peptide-1, INV-610, GUB021794, SHX-022, HDNO-1765, IP118, Q9P, BL OPUS II, DWRX-5003, ITCA-884, NPM 139. Semaglutide-IXB-401, HSP-005, Cbi-Ex4, SPN009, HSP-012C, BMS-686117, MET-0 6. NPM-159, MEDI-7219, CJC-1131, SDE-124, Dance-601, AS, AER-601, TH-0318, tapglutide, CS 872, Curaglutide, NN-9927, ITCA-880, Org-249305, HTI-2088, AC-3174, CW-7213, LP-9, CGEN-G11, FT228 ZY-D1 CRY-001 OP-286CR CAM-2036 AC2592 NN-9926 Val8-GLP-1 BK-0086 NN- 9925, P-5, ZYOG-1, SHR-2042, SXGLP1, PG-004, gSaxenda, Survodutide, HRS-9531, BGM-0 504, DD-01, Cotadutide, VK-2735, RAY1225, CT-388, Efinopegdutide, TB-001, Dapiglut ide, pemvidutide, olatorepatide, CT-868, PB-718, HDM-1005, HZ-010, NN-9490, UBT-25 1, DA-1726, LY-3493269, NN9542, Bamadutide, DR10627, ZP-2929, LY-3537031, THDBH1 Tirzepatide, BCGluExe, Pramlintide, THDBH121, MWN109, SPN-007, PB-2301, AC170222 OXM-101, HLB1-006, G-49, LM06, GEP44, MK-1462, AGM-217, PP18, RG-7697, CIN-210, HTL -023 ZP-GG-72 GEP12 PB-2309 LDM-3 HISHS-2001 OXM Pegapamodutide MK-8521 NN 9709 OAP-189 RO-6807952 SAR-438335 Oxyntomodulin MOD-6030 DA3-CH MEDI-416 6 CIN-209 SAR-441255 TKS-1225 DA-CH5 GUB06-046 RNTP-001A Recombinant exenatide-4, CagriSema, NNC0519-0130, ZT002, Diapin, DD-15, PF-1807, HLB1-015, DD-14, CMZ-371, DD02S, DR-10601, BZ-043B. NN-9928, NB-1001, VRS-859, ROSE-010, PSA-oxyntomodulin, NN- 9223. Glymera. PF-4856883. 4P-004. GB-7001. And / or, the small molecule chemical drug is HRS-7535, Orforglipron, NA-931, HDM1002, VCT220, Dagliron, MDR-001, SAL-0112, ECC-5004, Aleniglipron, AZD-9550, HZ-012, Lotiglipron, BI-3006337, ID-110521156, PF-06954522, XW-014, THDBH110, TERN-601, HMS 5678, SCO-094, CT-996, ASC-30, KP-405, TY-751, TY705, MLX-7006, NN1177, PGN-OB2, AX18, TT-OAD2, MLX7000, LuCI, GT-01123, GSBR-2nd Gen, RGT-274, ZP4165, BEBT-808, TTP-273, DD202-114, YGX1, WB4-24, YH-40863, CYRS-MD02, RV-003, MRANK111, Lotiglipron At least one of tromethamine, LSN-3318839, IGC-1A, AZD-0186, AST-6055, MK-5823, AB-301, HNC1031, Boc-5, FP-005, ID-11052, EP45, KR-69318, RDX-98940, RP-9056, K-579, TTP-054, JNJ-54728518, NNC-92041706, AGM-212, AZM-134, HD-7671, BHM-089, and LXM.2; And / or, the fusion protein drug is Supaglutide, SAL-015, JY-09, TG103, Efocipegtrutide, HEC-88473, MWN-101, DR10624, AMG-133, DR10628, SHR-1816, AP-026, Byetalog, GW002, YH-25724, MWN105, MWN-103, dulaglutide, GLP1-ELP-FGF21, TB-59-2, MWN115, rHSA-GLP-1, OGB-21502, GLP-1-Fc-FGF21 At least one of D1, OGB-21501, CVX-478, AMPE4L, GSK-2374697, DR10625, CNTO-3649, DR10619, E2HSA, CNTO-736, BA-5101, and RBS-006; and / or, the biosimilar drug is at least one of Bellarine, Lirafit, Tonbol, Lilupin, Jikeqin, BA-5101, CA-505, HDG-1901, TQF-3510, 4P-004, PG-001, MAR-531, DS-004, DS-006, PG-004, GB-7001, DS-012, RBS-006, and RD-12014; And / or, the hormone drug is at least one of NovoElix, Saiyining, HR-17031, SL-209, Icosema, Amycretin, GLP-06, ACT-1003, BL OPUS IV, OXM-001, MBX-4291, GLP-1CCM, JNASE-7001, and BEM-041; and / or, the chemical drug is at least one of APH01727, DD-03, OXM-104, HSP-016, HISHS-3001, XFL6, D-314, CY-5, DA-JC1, and DA-JC4; and / or, the biopharmaceutical is at least one of Bofanglutide, LBT-6030, VTC-G15, AM-1118, ME001, SN-006, SYNT-101, ATBB-22, XW-015, PF-4603629, NN-9277, BEM-012, HYBR-011, LY-548806, and ZP-3022; and / or, the recombinant protein drug is at least one of enoglutide, ZT-003, ZT-007, and HTB-C041; and / or, the adeno-associated virus gene therapy drug is at least one of AAV-Ex-4, KT-A522, and rAd-GLP-1; And / or, the antibody fusion protein drug is at least one of ZX2010 and ZX2021; and / or, the gene therapy drug is at least one of Y002 and RMD-1202; And / or, the conjugated drug is at least one of SNC-001 and GLP-1-MK-801; and / or, the mRNA drug is HFG1; and / or, the monoclonal antibody drug is glutarizumab; and / or, the bispecific antibody drug is GMA-106; And / or, the mesenchymal stem cell therapy drug is a fat stem cell injection solution with high expression of human GLP-1 and FGF21 dual factors; And / or, the protein drug is ZT-005.

16. The pharmaceutical composition according to any one of claims 11 to 15, characterized in that: The THR-β agonist is selected from compound 2, and the GLP-1 receptor agonist is selected from at least one of semaglutide, telpotide, and orforglipron; the structural formula of compound 2 is 17. The pharmaceutical composition according to any one of claims 11 to 15, characterized in that: When the THR-β agonist and / or GLP-1 receptor agonist is selected from small molecule chemical drugs, the small molecule chemical drugs are deuterated compounds thereof.

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