Drug combination for preventing and / or treating obesity

Abstract

The present invention relates to a drug combination for preventing and / or treating obesity. The drug combination is a drug combination of a THR-β agonist and a GLP-1 receptor agonist. The drug combination can achieve a synergistic effect, reduces weight by promoting fat metabolism, reducing fat content, controlling appetite, slowing gastric emptying, increasing satiety, etc., can be used as an effective strategy for solving obesity problems, and has wide prospects for application.

Description

A combined medicament for preventing and / or treating obesity TECHNICAL FIELD

[0001] The present application belongs to the field of chemical medicine, and particularly relates to a combined medicament for preventing and / or treating obesity. BACKGROUND

[0002] Obesity refers to excessive total fat content and / or increased local content and abnormal distribution in the body, and is a chronic metabolic disease caused by the combined action of genetic and environmental factors. According to the World Health Organization, a body mass index (BMI) of 25.0-29.9 kg·m –2 belongs to overweight, and a BMI of 30 kg·m –2 belongs to obesity. According to the Chinese Obesity Expert Group, a BMI of 24.0-27.9 kg·m –2 belongs to overweight, and a BMI of 28 kg·m –2 belongs to obesity. Obesity can cause a series of health problems, such as increasing the risk of hypertension, diabetes, cardiovascular and cerebrovascular diseases, and tumors and other chronic diseases, and can also cause social and psychological problems, and has become one of the major public health problems in China. Therefore, early intervention of obesity is of great significance for preventing and treating the occurrence and development of its complications.

[0003] The lipid-lowering and weight-reducing effects of thyroid hormones and thyroid hormone analogs have been a research hotspot. Recent animal studies have found that thyroid hormone receptor beta (THRbeta) agonists such as KB-141 and GC-1 can increase tissue oxygen consumption, reduce fat content, and reduce body weight. In addition, such preparations can also reduce the levels of low-density lipoprotein-cholesterol, lipoprotein a, and triglycerides, and effectively reduce the risk of atherosclerosis. At the same time, these drugs can accelerate metabolism without increasing food intake or causing cardiovascular adverse reactions such as increased heart rate. Therefore, THRbeta 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 agonists (GLP-1RAs) can, on the one hand, intelligently respond to hyperglycemia, increase insulin secretion, and inhibit the release of glucagon, helping the body to more effectively regulate blood glucose levels when blood glucose rises, and are used for the treatment of type 2 diabetes mellitus (T2DM); on the other hand, they act on the central and peripheral nervous systems to control appetite and delay gastric emptying, thereby increasing satiety and reducing food intake, achieving weight loss. Liraglutide and semaglutide injection belong to GLP-1RA preparations, and were approved by the FDA in 2014 and 2021, respectively, for the treatment of obesity, with excellent weight loss effects.

[0005] Although the current weight loss drugs have achieved certain effects, there are still serious adverse reactions, resulting in poor effects. 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 to bring more treatment options for overweight and obese people. SUMMARY

[0006] In view of the defects in the prior art, the present application provides a combination 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 combination drug for preventing and / or treating obesity, wherein the combination drug is a THR-β agonist and a GLP-1 receptor agonist.

[0008] Preferably, the combination drug is a THR-β agonist and a GLP-1 receptor agonist used separately or simultaneously.

[0009] Preferably, 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).

[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 drug is at least one of MGL-3196, thyroxine, sodium liothyronine, tiratricol, 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 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, CNPT-101101.

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

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

[0014] wherein X, Y are selected from halogen.

[0015] Preferably, the structural formula of Formula I is as follows:

[0016] Preferably, the GLP-1 receptor agonist is at least one of a polypeptide drug, a small molecule chemical drug, a fusion protein drug, a biosimilar drug, a hormone drug, a chemical drug, a biological drug, a recombinant protein drug, an adeno-associated virus gene therapy drug, an antibody fusion protein drug, a gene therapy drug, a conjugate drug, an mRNA drug, a monoclonal antibody drug, a bispecific antibody drug, a mesenchymal stem cell therapy drug, and a protein drug.

[0017] The polypeptide drug is semaglutide, peglomitatide, dulaglutide, lixisenatide, exenatide, QLG 2065, liraglutide, peglispro, efpeglenatide, NLY-01, albiglutide, taspoglutide, medinatide, retaglutide, froniglutide, Gln28Exenatide, ANY002, utreglutide, NNC0113-6856, pegsebrenatide, Glucagon-like peptide-1, INV-610, GUB021794, SHX-022, HDNO-1765, IP118, Q9P, BLOPUS II, DWRX-5003, ITCA-884, NPM 139, Semaglutide-IXB-401, HSP-005, Cbi-Ex4, SPN009, HSP-012C, BMS-686117, MET-06, NPM-159, MEDI-7219, CJC-1131, SDE-124, Dance-601, AS, AER-601, TH-0318, taspoglutide, CS 872, curaglutide, NN-9927, ITCA-880, Org-249305, HTI-2088, AC-3174, CW-7213, LP-9, CGEN-G11, FT 228, 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-0504, DD-01, Cotadutide, VK-2735, RAY1225, CT-388, Efinopegdutide, TB-001, Dapiglutide, Pemvidutide, Olatorepatide, CT-868, PB-718, HDM-1005, HZ-010, NN-9490, UBT-251, DA-1726, LY-3493269, NN9542, Bamadutide, DR10627, ZP-2929, LY-3537031, THDBH120, 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-4166, CIN-209, SAR-441255, TKS-1225, DA-CH5, GUB06-046, RNTP-001A, Benalux, 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, RD-12014, at least one of

[0018] and / or the small molecule chemical drug is at least one of HRS-7535, Orforglipron, NA-931, HDM1002, VCT220, Dapagliflozin, 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 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, LXM.2;

[0019] and / or the fusion protein drug is at least one of Suparutide, 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 D1, OGB-21501, CVX-478, AMPE4L, GSK-2374697, DR10625, CNTO-3649, DR10619, E2HSA, CNTO-736, BA-5101, RBS-006;

[0020] and / or the biological similar drug is at least one of Belerlin, Lirafit, Tongbolin, Lirupin, 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, RD-12014;

[0021] and / or the hormone drug is at least one of Novo Nordisk, Saiyining, HR-17031, SL-209, Icosema, Amycretin, GLP-06, ACT-1003, BLOPUS IV, OXM-001, MBX-4291, GLP-1CCM, JNASE-7001, BEM-041;

[0022] 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, DA-JC4;

[0023] and / or the biological drug 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, ZP-3022;

[0024] and / or the recombinant protein drug is at least one of Inogralupeptide, ZT-003, ZT-007, HTB-C041;

[0025] and / or the adeno-associated virus gene therapy drug is at least one of AAV-Ex-4, KT-A522, rAd-GLP-1;

[0026] and / or the antibody fusion protein drug is at least one of ZX2010, ZX2021;

[0027] and / or the gene therapy drug is at least one of Y002, RMD-1202;

[0028] and / or the conjugated drug is at least one of SNC-001, GLP-1-MK-801;

[0029] and / or the mRNA drug is HFG1;

[0030] and / or the monoclonal antibody drug is golimumab;

[0031] and / or the bispecific antibody drug is GMA-106;

[0032] and / or the mesenchymal stem cell therapy drug is human GLP-1 and FGF21 double factor high expression adipose stem cell injection;

[0033] and / or the protein drug is ZT-005.

[0034] Preferably, when the THR-β agonist and / or GLP-1 receptor agonist is selected from a small molecule chemical drug, the small molecule chemical drug is a deuterium compound thereof.

[0035] Preferably, the THR-β agonist is selected from compound 2, and the GLP-1 receptor agonist is selected from at least one of semaglutide, tirzepatide and orforglipron; the structural formula of the compound 2 is

[0036] The present application also provides a use of the above-mentioned combination drug in the preparation of a medicament for preventing and / or treating obesity.

[0037] The present application also provides a pharmaceutical composition for preventing and / or treating obesity, which is prepared by adding pharmaceutically acceptable adjuvants or auxiliary ingredients to a THR-β agonist and a GLP-1 receptor agonist as active 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).

[0038] Preferably, the THR-β agonist is selected from at least one of a small molecule chemical drug and a chemical drug;

[0039] The small molecule chemical drug is at least one of Selumetinib, Thyroxine, Sodium Iodide, Tirilazad, 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 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, CNPT-101101.

[0040] And / or, the chemical drug is at least one of CVI-2742, Cyta-001, KTA-574.

[0041] Preferably, the THR-β agonist is as shown in Formula I:

[0042] wherein X, Y are selected from halogen.

[0043] Preferably, the structure of Formula I is as follows:

[0044] Preferably, the GLP-1 receptor agonist is at least one of a polypeptide drug, a small molecule chemical drug, a fusion protein drug, a biosimilar drug, a hormone drug, a chemical drug, a biological drug, a recombinant protein drug, an adeno-associated virus gene therapy drug, an antibody fusion protein drug, a gene therapy drug, a conjugate drug, an mRNA drug, a monoclonal antibody drug, a bispecific antibody drug, a mesenchymal stem cell therapy drug, and a protein drug.

[0045] The polypeptide drug is semaglutide, peglomitatide, dulaglutide, lixisenatide, exenatide, QLG 2065, liraglutide, peglispro, efpeglenatide, NLY-01, albiglutide, taspoglutide, medinatide, retaglutide, froniglutide, Gln28Exenatide, ANY002, utreglutide, NNC0113-6856, pegsebrenatide, Glucagon-like peptide-1, INV-610, GUB021794, SHX-022, HDNO-1765, IP118, Q9P, BLOPUS II, DWRX-5003, ITCA-884, NPM 139, Semaglutide-IXB-401, HSP-005, Cbi-Ex4, SPN009, HSP-012C, BMS-686117, MET-06, NPM-159, MEDI-7219, CJC-1131, SDE-124, Dance-601, AS, AER-601, TH-0318, taspoglutide, CS 872, curaglutide, NN-9927, ITCA-880, Org-249305, HTI-2088, AC-3174, CW-7213, LP-9, CGEN-G11, FT 228, 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-0504, DD-01, Cotadutide, VK-2735, RAY1225, CT-388, Efinopegdutide, TB-001, Dapiglutide, Pemvidutide, Olatorepatide, CT-868, PB-718, HDM-1005, HZ-010, NN-9490, UBT-251, DA-1726, LY-3493269, NN9542, Bamadutide, DR10627, ZP-2929, LY-3537031, THDBH120, 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-4166, CIN-209, SAR-441255, TKS-1225, DA-CH5, GUB06-046, RNTP-001A, Benalux, 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, RD-12014, at least one of

[0046] and / or the small molecule chemical drug is at least one of HRS-7535, Orforglipron, NA-931, HDM1002, VCT220, Dapagliflozin, 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 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, LXM.2;

[0047] and / or the fusion protein drug is at least one of Suparutide, 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 D1, OGB-21501, CVX-478, AMPE4L, GSK-2374697, DR10625, CNTO-3649, DR10619, E2HSA, CNTO-736, BA-5101, RBS-006;

[0048] and / or the biological similar drug is at least one of Belerlin, Lirafit, Tongbolin, Lirupin, 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, RD-12014;

[0049] and / or the hormone drug is at least one of Novo Nordisk, Saiyining, HR-17031, SL-209, Icosema, Amycretin, GLP-06, ACT-1003, BLOPUS IV, OXM-001, MBX-4291, GLP-1CCM, JNASE-7001, BEM-041;

[0050] 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, DA-JC4;

[0051] and / or the biological drug 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, ZP-3022;

[0052] and / or the recombinant protein drug is at least one of Inogralupeptide, ZT-003, ZT-007, HTB-C041;

[0053] and / or the adeno-associated virus gene therapy drug is at least one of AAV-Ex-4, KT-A522, rAd-GLP-1;

[0054] and / or the antibody fusion protein drug is at least one of ZX2010, ZX2021;

[0055] and / or the gene therapy drug is at least one of Y002, RMD-1202;

[0056] and / or the conjugated drug is at least one of SNC-001, GLP-1-MK-801;

[0057] and / or the mRNA drug is HFG1;

[0058] and / or the monoclonal antibody drug is golimumab;

[0059] and / or the bispecific antibody drug is GMA-106;

[0060] and / or the mesenchymal stem cell therapy drug is human GLP-1 and FGF21 double factor high expression adipose stem cell injection;

[0061] and / or the protein drug is ZT-005.

[0062] Preferably, the THR-beta agonist is selected from compound 2, the GLP-1 receptor agonist is selected from at least one of semaglutide, tirzepatide, orforglipron; the structural formula of the compound 2 is

[0063] Preferably, when the THR-beta agonist and / or GLP-1 receptor agonist is selected from a small molecule chemical drug, the small molecule chemical drug is a deuterium compound thereof.

[0064] The present application first combines the THR-beta agonist with the GLP-1 receptor agonist, has a synergistic effect, can significantly reduce the fat content while not increasing the muscle loss, realizes high-quality weight loss, is used for preventing and / or treating obesity, and has a wide application prospect.

[0065] Among them, part of the chemical structural formula of the THR-beta agonist is shown in Table 1; part of the chemical structural formula of the GLP-1 receptor agonist is shown in Table 2.

[0066] Table 1 part of the THR-beta agonist and its chemical structural formula

[0067] Table 2 part of the GLP-1 receptor agonist and its chemical structural formula

[0068] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and conventional means in the art, other various forms of modification, replacement or change can be made without departing from the above technical idea of the present application.

[0069] The above content of the present application will be further illustrated in detail by the following embodiment form. However, this should not be understood as the scope of the above subject matter of the present application being limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0070] Figure 1 is the change of body weight of mice during the administration of high-fat diet induced obesity model.

[0071] Figure 2 is the change of muscle and fat mass of mice after 42 days of administration compared with before administration.

[0072] Figure 3 is the content of TG and TC in liver of mice after 42 days of administration.

[0073] Figure 4 is the content of TG, TC and LDL-c in blood of mice after 42 days of administration.

[0074] Figure 5 is the Respiratory Exchange Ratio (RER) of energy consumption of mice after 42 days of administration. DETAILED DESCRIPTION

[0075] In the following examples and experimental examples, the reagents and materials not specifically stated are commercially available.

[0076] The structural formula of the THR-β agonist compound 2 is

[0077] Example 1 Combination drug for treating obesity

[0078] The present example provides a combination drug for treating obesity, which is a combination drug comprising 30 mg of compound 2 and 0.12 mg of semaglutide.

[0079] Example 2 Combination drug for treating obesity

[0080] The present example provides a combination drug for treating obesity, which is a combination drug comprising 15 mg of compound 2 and 400 mg of semaglutide.

[0081] Example 3 Combination drug for treating obesity

[0082] The present example provides a combination drug for treating obesity, which is a combination drug comprising 150 mg of compound 2 and 3 mg of semaglutide.

[0083] Example 4 Combination drug for treating obesity

[0084] The present example provides a combination drug for treating obesity, which is a combination drug comprising 200 mg of compound 2 and 0.04 mg of semaglutide.

[0085] Example 5 Combination drug for treating obesity

[0086] The present example provides a combination drug for treating obesity, which is a combination drug comprising 10 mg of compound 2 and 100 mg of semaglutide.

[0087] The technical solutions of the present application are further illustrated by experiments.

[0088] Experimental Example 1: Pharmacodynamic effect of THR-β agonist compound 2 combined with GLP-1 receptor agonist semaglutide in an obese mouse model

[0089] I. Experimental methods

[0090] DIO mice were induced by 60% high-fat diet to construct an obesity model, and the in vivo pharmacodynamics of compound 2 combined with semaglutide was evaluated. 60 DIO mice were randomly divided into 6 groups: vehicle group, compound 2 30mg / kg group, semaglutide 30nmol / kg group, semaglutide 3nmol / kg+compound 2 30mg / kg group, semaglutide 30nmol / kg+compound 2 3mg / kg group, and semaglutide 30nmol / kg+compound 2 30mg / kg group. The structural formula of compound 2 is

[0091] 10 normal diet-fed C57BL / 6J mice were used as negative control group (Chow vehicle group). Semaglutide and compound 2 (Compound 2) were administered subcutaneously and orally once a day, respectively, 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.

[0092] II. Experimental results

[0093] The body weight change of mice during the experiment is shown in Figure 1: compared with the Chow vehicle group, the body weight of DIO mice in the vehicle group increased. The body weight of mice in the Compound 2 30 mg / kg group decreased compared with the vehicle group, and the body weight of mice in the semaglutide 30 nmol / kg group decreased significantly compared with the vehicle group; the body weight of mice in the semaglutide 3 nmol / kg + Compound 2 30 mg / kg group and the semaglutide 30 nmol / kg + Compound 2 3 mg / kg group decreased more significantly compared with the semaglutide 30 nmol / kg group; the body weight of mice in the semaglutide 30 nmol / kg + Compound 2 30 mg / kg group decreased most significantly compared with the semaglutide 30 nmol / kg group, and showed a dose-dependent manner; the results showed that the combination of Compound 2 and semaglutide could produce a synergistic effect in the treatment of obesity.

[0094] The results of the body fat ratio of mice are shown in Figure 2: 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 the mice fed with normal diet, and the muscle content of each group was close. At the end of 42 days of administration, the semaglutide 30 nmol / kg group reduced 1.7 g of muscle mass, and each combination group did not significantly exacerbate muscle loss; on the other hand, the Compound 2 30 mg / kg group reduced 2.5 g of fat mass, the semaglutide 30 nmol / kg group reduced 6.2 g of fat mass, the semaglutide 3 nmol / kg + Compound 2 30 mg / kg group reduced 12.8 g of fat mass, the semaglutide 30 nmol / kg + Compound 2 3 mg / kg group reduced 12.3 g of fat mass; and the semaglutide 30 nmol / kg + Compound 2 30 mg / kg group reduced 15.0 g of fat mass. The results showed that the combination of Compound 2 and semaglutide could significantly reduce fat content without exacerbating muscle loss, and the effect was significantly stronger than that of any single component alone.

[0095] The mouse liver biochemical results are shown in Figure 3. At the end of 42 days of administration, the TG and TC contents of each administration group were significantly decreased compared with the Vehicle group (P < 0.0001). Compared with the semaglutide 30 nmol / kg single-drug administration group, the TG and TC contents of the Compound 2 30 mg / kg group and each combination administration group were further significantly decreased. Among them, the TC content of the semaglutide 3 nmol / kg + Compound 2 30 mg / kg group was most significantly decreased, and the TG content of the semaglutide 30 nmol / kg + Compound 2 3 mg / kg group was most significantly decreased. The results show that the combination of drugs can significantly reduce the TG and TC contents in the liver of mice.

[0096] The mouse blood biochemical results are shown in Figure 4. At the end of 42 days of administration, the TG, TC, and LDL-c contents of each administration group were significantly decreased compared with the Vehicle group. Compared with the semaglutide 30 nmol / kg single-drug administration group, the TG, TC, and LDL-c contents of the Compound 2 30 mg / kg group and each combination administration group were further significantly decreased. Among them, the TG, TC, and LDL-c contents of the semaglutide 3 nmol / kg + Compound 2 30 mg / kg group were most significantly decreased. The results show that the combination of drugs can significantly reduce the TG, TC, and LDL-c contents in the blood of mice.

[0097] The mouse energy consumption results are shown in Figure 5. At the end of 42 days of administration, the Respiratory Exchange Ratio (RER) of the Vehicle, semaglutide 30 nmol / kg, Compound 2 30 mg / kg, and semaglutide 30 nmol / kg combined with Compound 2 30 mg / kg groups was evaluated. The results show that the combination administration group can improve energy consumption, and the effect is significantly stronger than that of any single group, having a significant synergistic effect.

[0098] The combination of Compound 2 and tirzepatide has a similar synergistic effect on weight loss. The combination of Compound 2 and Orforglipron also has a similar synergistic effect on weight loss.

[0099] In summary, the combination of the THR-β agonist represented by compound 2 and the GLP-1 agonist represented by semaglutide can significantly reduce the body weight of obese animals, significantly reduce the TG, TC and LDL-c content, increase energy consumption, achieve a higher muscle / fat ratio, achieve a high-quality fat loss effect, and have a synergistic effect. Therefore, the combination of the THR-β agonist and the GLP-1 receptor agonist can effectively prevent and / or treat obesity, and has a broad application prospect.

Claims

1. A combination medicament for preventing and / or treating obesity, comprising: The combination drug is a THR-β agonist and a GLP-1 receptor agonist. ​ 2. The combination of claim 1, wherein: The combination drug is a THR-β agonist and a GLP-1 receptor agonist.

3. The combination of claim 1, wherein: 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).

4. The combination of claim 1, wherein: The THR-β agonist is selected from at least one of small molecule chemical drugs and chemical drugs; The small molecule chemical drug is at least one of Sobetirome, Thyroxine, Sodium Iodide, Tiratricol, 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 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, CNPT-101101; And / or, the chemical drug is at least one of CVI-2742, Cyta-001, KTA-574.

5. The combination of claim 1, wherein The THR-beta agonist is represented by Formula I: X and Y are selected from halogen.

6. The combination of claim 5, wherein The structural formula of the formula I is as follows:

7. The combination of claim 1, wherein: The GLP-1 receptor agonist is selected from at least one of polypeptide drugs, small molecule chemical drugs, fusion protein drugs, biosimilars, hormone drugs, chemical drugs, biological drugs, recombinant protein drugs, adeno-associated virus gene therapy drugs, antibody fusion protein drugs, gene therapy drugs, conjugate drugs, mRNA drugs, monoclonal antibody drugs, bispecific antibody drugs, mesenchymal stem cell therapy drugs, and protein drugs. The polypeptide drug is semaglutide, peglomitatide, dulaglutide, lixisenatide, exenatide, QLG 2065, liraglutide, peglispro, efpeglenatide, NLY-01, albiglutide, taspoglutide, medinatide, retaglutide, froniglutide, Gln28Exenatide, ANY002, utreglutide, NNC0113-6856, pegsebrenatide, Glucagon-like peptide-1, INV-610, GUB021794, SHX-022, HDNO-1765, IP118, Q9P, BLOPUS II, DWRX-5003, ITCA-884, NPM 139, Semaglutide-IXB-401, HSP-005, Cbi-Ex4, SPN009, HSP-012C, BMS-686117, MET-06, NPM-159, MEDI-7219, CJC-1131, SDE-124, Dance-601, AS, AER-601, TH-0318, taspoglutide, CS 872, curaglutide, NN-9927, ITCA-880, Org-249305, HTI-2088, AC-3174, CW-7213, LP-9, CGEN-G11, FT 228, 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-0504, DD-01, Cotadutide, VK-2735, RAY1225, CT-388, Efinopegdutide, TB-001, Dapiglutide, Pemvidutide, Olatorepatide, CT-868, PB-718, HDM-1005, HZ-010, NN-9490, UBT-251, DA-1726, LY-3493269, NN9542, Bamadutide, DR10627, ZP-2929, LY-3537031, THDBH120, 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-4166, CIN-209, SAR-441255, TKS-1225, DA-CH5, GUB06-046, RNTP-001A, Benalux, 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, RD-12014; and / or the small molecule chemical drug is at least one of HRS-7535, Orforglipron, NA-931, HDM1002, VCT220, Dapagliflozin, 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 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, LXM.2; and / or the fusion protein drug is at least one of Suparutide, 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 D1, OGB-21501, CVX-478, AMPE4L, GSK-2374697, DR10625, CNTO-3649, DR10619, E2HSA, CNTO-736, BA-5101, RBS-006; And / or, the biological similar drug is at least one of Beloranib, Lirafit, Unibody, Liraglutide, Jelcobin, 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, RD-12014; And / or, the hormone drug is at least one of Novo Nordisk, Symlin, HR-17031, SL-209, Icosema, Amycretin, GLP-06, ACT-1003, BLOPUS IV, OXM-001, MBX-4291, GLP-1 CCM, JNASE-7001, 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, DA-JC4; And / or, the biological drug 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, ZP-3022; And / or, the recombinant protein drug is at least one of Inogropeptide, ZT-003, ZT-007, HTB-C041; And / or, the adeno-associated virus gene therapy drug is at least one of AAV-Ex-4, KT-A522, rAd-GLP-1; And / or, the antibody fusion protein drug is at least one of ZX2010, ZX2021; And / or, the gene therapy drug is at least one of Y002, RMD-1202; And / or, the conjugated drug is at least one of SNC-001, GLP-1-MK-801; And / or, the mRNA drug is HFG1; And / or, the monoclonal antibody drug is Glucartamab; And / or, the bispecific antibody drug is GMA-106; And / or, the mesenchymal stem cell therapy drug is human GLP-1 and FGF21 double factor high expression adipose stem cell injection; And / or, the protein drug is ZT-005.

8. The combination according to any one of claims 1 to 7, wherein: When the THR-β agonist and / or GLP-1 receptor agonist is selected from a small molecule chemical drug, the small molecule chemical drug is a deuterium compound thereof.

9. The combination according to any one of claims 1 to 7, wherein: The THR-beta agonist is selected from the group consisting of Compound 2, and the GLP-1 receptor agonist is selected from the group consisting of semaglutide, tirzepatide, and orforglipron; and the structural formula of Compound 2 is 10. Use of the combination drug according to any one of claims 1-9 in the preparation of a drug for preventing and / or treating obesity.

11. A pharmaceutical composition for preventing and / or treating obesity, characterized by comprising the compound of claim 1 as an active ingredient. It is made of THR-beta agonist and GLP-1 receptor agonist as active ingredients, and pharmaceutically acceptable adjuvant or auxiliary ingredients; the weight ratio of the THR-beta agonist and GLP-1 receptor agonist is (15-150):(3-400) or (10-200):(0.04-100).

12. The pharmaceutical composition according to claim 11, characterized by: The THR-beta agonist is selected from at least one of small molecule chemical drugs and chemical drugs; The small molecule chemical drug is at least one of Sobetirome, Thyroxine, Sodium Iodide, Tiratricol, 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 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, CNPT-101101; And / or, the chemical drug is at least one of CVI-2742, Cyta-001, KTA-574.

13. The pharmaceutical composition according to claim 11, characterized by The THR-beta agonist is represented by Formula I: X and Y are selected from halogen.

14. The pharmaceutical composition according to claim 11, characterized by The structural formula of the formula I is as follows:

15. The pharmaceutical composition according to claim 11, characterized by: The GLP-1 receptor agonist is selected from at least one of polypeptide drugs, small molecule chemical drugs, fusion protein drugs, biosimilars, hormone drugs, chemical drugs, biological drugs, recombinant protein drugs, adeno-associated virus gene therapy drugs, antibody fusion protein drugs, gene therapy drugs, conjugate drugs, mRNA drugs, monoclonal antibody drugs, bispecific antibody drugs, mesenchymal stem cell therapy drugs, and protein drugs. The polypeptide drug is semaglutide, peglomitatide, dulaglutide, lixisenatide, exenatide, QLG 2065, liraglutide, peglispro, efpeglenatide, NLY-01, albiglutide, taspoglutide, medinatide, retaglutide, froniglutide, Gln28Exenatide, ANY002, utreglutide, NNC0113-6856, pegsebrenatide, Glucagon-like peptide-1, INV-610, GUB021794, SHX-022, HDNO-1765, IP118, Q9P, BLOPUS II, DWRX-5003, ITCA-884, NPM 139, Semaglutide-IXB-401, HSP-005, Cbi-Ex4, SPN009, HSP-012C, BMS-686117, MET-06, NPM-159, MEDI-7219, CJC-1131, SDE-124, Dance-601, AS, AER-601, TH-0318, taspoglutide, CS 872, curaglutide, NN-9927, ITCA-880, Org-249305, HTI-2088, AC-3174, CW-7213, LP-9, CGEN-G11, FT 228, 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-0504, DD-01, Cotadutide, VK-2735, RAY1225, CT-388, Efinopegdutide, TB-001, Dapiglutide, Pemvidutide, Olatorepatide, CT-868, PB-718, HDM-1005, HZ-010, NN-9490, UBT-251, DA-1726, LY-3493269, NN9542, Bamadutide, DR10627, ZP-2929, LY-3537031, THDBH120, 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-4166, CIN-209, SAR-441255, TKS-1225, DA-CH5, GUB06-046, RNTP-001A, Benalux, 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, RD-12014; and / or the small molecule chemical drug is at least one of HRS-7535, Orforglipron, NA-931, HDM1002, VCT220, Dapagliflozin, 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 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, LXM.2; and / or the fusion protein drug is at least one of Suparutide, 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 D1, OGB-21501, CVX-478, AMPE4L, GSK-2374697, DR10625, CNTO-3649, DR10619, E2HSA, CNTO-736, BA-5101, RBS-006; And / or, the biological similar drug is at least one of Belinacip, Lirafit, Unibrol, Liraplus, Jikexin, 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, RD-12014; And / or, the hormone drug is at least one of Novo Nordisk, Sainening, HR-17031, SL-209, Icosema, Amycretin, GLP-06, ACT-1003, BLOPUS IV, OXM-001, MBX-4291, GLP-1CCM, JNASE-7001, 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, DA-JC4; And / or, the biological drug 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, ZP-3022; And / or, the recombinant protein drug is at least one of Inogropeptide, ZT-003, ZT-007, HTB-C041; And / or, the adeno-associated virus gene therapy drug is at least one of AAV-Ex-4, KT-A522, rAd-GLP-1; And / or, the antibody fusion protein drug is at least one of ZX2010, ZX2021; And / or, the gene therapy drug is at least one of Y002, RMD-1202; And / or, the conjugated drug is at least one of SNC-001, GLP-1-MK-801; And / or, the mRNA drug is HFG1; And / or, the monoclonal antibody drug is Glutazolimab; And / or, the bispecific antibody drug is GMA-106; And / or, the mesenchymal stem cell therapy drug is human GLP-1 and FGF21 double factor high expression adipose stem cell injection; 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-beta agonist is selected from the group consisting of Compound 2, and the GLP-1 receptor agonist is selected from the group consisting of semaglutide, tirzepatide, and orforglipron; and 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 a small molecule chemical drug, the small molecule chemical drug is a deuterium compound thereof.

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