Novel medical application of terphenyl compound

Abstract

The invention relates to a novel medical application of a terphenyl compound as an HIF inhibitor, belongs to the field of medicinal chemistry, and particularly relates to a terphenyl compound which comprises a stereoisomer, a geometric isomer, a tautomer, nitrogen oxide, hydrate, solvate, metabolite and ester of the terphenyl compound. The pharmaceutically acceptable salt or the prodrug thereof and the pharmaceutical composition containing the compound are used as medicines, especially used for treating and / or preventing related diseases caused by HIF, and have good application prospects and commercial values.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a terphenyl compound, a composition and an application, wherein the compound or the composition has the activity of being a hypoxia-inducible factor (HIF) inhibitor and can be used for treating HIF-related diseases. Background Art

[0002] Hypoxia-inducible factor (HIF) is a nuclear protein with transcriptional activity, which plays a key role in the process of cell adaptation to the hypoxic environment. It is a heterodimer composed of HIF-1α and HIF-1β subunits. Under normal oxygen partial pressure, the HIF-α subunit will be hydroxylated by prolyl hydroxylase (PHD) and then rapidly degraded by the ubiquitin-proteasome pathway (Bruick, R.K. Science. 2001, 294: 1337-1340; Kamura, T. Proc. Natl. Acad. Sci. U.S.A. 2000, 97: 10430-10435). However, under hypoxic conditions, the activity of PHD is inhibited, the HIF-α subunit is stabilized and binds to the HIF-1β subunit to form an active HIF transcription factor, which translocates into the nucleus and initiates the transcription of a series of hypoxia-responsive genes (Semenza, G.L. Trends Pharmacol. Sci. 2012, 33: 207-214; Wigerup, C. Pharmacol. Ther. 2016, 164: 152-169). These gene products play a crucial role in improving hypoxia, promoting angiogenesis, regulating energy metabolism, etc.

[0003] HIF is associated with a variety of diseases, and the abnormal activation or inactivation of HIF is closely related to the occurrence and development of many diseases. In tumor diseases, in order to adapt to the hypoxic environment caused by rapid proliferation, tumor cells will activate the HIF signaling pathway (Ke, Q. Molecular Pharmacology 2006, 70(5): 1469-1480; Li, H. Adv. Sci. 2023, 2301071). HIF can promote tumor angiogenesis, enabling tumor cells to obtain sufficient oxygen and nutrients. At the same time, it can also regulate the metabolism of tumor cells, enabling them to adapt to the hypoxic environment and enhancing their invasion and metastasis abilities. For example, in various solid tumors such as breast cancer, liver cancer, and lung cancer, high expression of HIF-1α has been found to be associated with poor prognosis of tumors (Moon, E. J. Antioxid. Redox Signaling. 2007, 9: 1237-1294; Chen, C. OncoTarget. 2017, 8: 46691-46703; Kim, B. J. Transl. Med. 2013, 11: 185). Therefore, HIF-1 is considered a promising target for developing new anti-cancer metastasis therapies. Additionally, in ischemic diseases such as myocardial ischemia and cerebral ischemia, moderate activation of the HIF pathway can promote angiogenesis and tissue repair, with potential therapeutic value (Zimna, A. BioMed Research International 2015, 1-14).

[0004] Terphenyls are mainly derived from fungi and actinomycetes and mainly exist in the form of p-terphenyls in nature. The structural feature of terphenyl is composed of a central benzene ring B and two phenyl groups (ring A and C) substituted at the para positions of benzene ring B. So far, more than 230 p-terphenyls have been identified, and the number is still increasing. This compound exhibits various biological activities such as anti-inflammatory, antibacterial, antioxidant, and α-glucosidase inhibitory effects (Zhou G. Marine Life Science & Technology. 2022, 4: 62–73), but no activity of inhibiting HIF has been reported, and its application in the preparation of drugs for preventing or treating HIF-mediated diseases has not been seen either. Summary of the Invention

[0005] Only some aspects of the present invention are generally described below and are not limited thereto. These aspects and other parts are described more completely later. All references in this specification are incorporated herein by reference in their entirety. When there are differences between the disclosure of this specification and the cited literature, the disclosure of this specification shall prevail.

[0006] The present invention provides a terphenyl compound for treating diseases related to HIF activation, including but not limited to tumor growth and metastasis, tumor drug resistance, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), diabetic nephropathy, non-alcoholic fatty liver disease (NAFLD), etc. The compounds of the present invention are easy to prepare, have stable properties and strong activities, and thus have good clinical application prospects.

[0007] Specifically:

[0008] On the one hand, the present invention relates to a terphenyl compound, characterized in that it is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I), especially for use as a HIF inhibitor, characterized in that the compound has the following structure:

[0009] The specific structure is as follows:

[0010]

[0011] Compound 1 has been disclosed in the literature

[0012] Xi-Zhen Cao, Bo-Qi Zhang, Cui-Fang Wang, Jun-Na Yin, Waqas Haider, Mei-Yan Wei and Ling Lu. A Terphenyllin Derivative CHNQD-00824 from the Marine Compound Library Induced DNA Damage as a Potential Anticancer Agent [J] Marine Drugs, 2023, 21, 512.

[0013] Compounds 2-4 have been disclosed in the literature

[0014] Xue-Qing Zhang,Xiao-Feng Mou,Ning Mao,Jie-Jie Hao,Ming Liu,Ji-YongZheng,Chang-Yun Wang,Yu-Cheng Gu,and Chang-Lun Shao.Design,semisynthesis,a-glucosidase inhibitory,cytotoxic,and antibacterial activities of p-terphenylderivatives[J]European Journal of Medicinal Chemistry,2018,146,232-244.

[0015] Compound 5 has been disclosed in the literature

[0016] Cui-Fang Wang,Jie Hu,Xiao-Ying Liu,Yue-Xuan Qi,Xi-Zhen Cao,Wen-JingSun,Ya-Jie Cheng,Mei-Yan Wei,Ji-Yong Zheng,Chang-Lun Shao.Discovery newmarine-derived terphenyllin derivatives as potential antifoulants throughstructural optimization[J]Bioorganic Chemistry,2025,159,108389

[0017] On the other hand, the present invention relates to a pharmaceutical composition comprising the compound disclosed in the present invention. The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

[0018] The term "pharmaceutically acceptable salt" in the present invention refers to a non-toxic addition salt of an inorganic or organic acid and / or base; see "Salt selection for basic drugs", International Journal ofPharmaceutics. 1986, 33, 201–217.

[0019] Compared with the prior art, the beneficial effects of the present invention are:

[0020] The present invention discloses for the first time that a terphenyl compound can significantly reduce the reaction of HIF overexpression caused by hypoxia, and has good application prospects and commercial value.

[0021] The "HIF-related disease" refers to a series of diseases caused by overexpression or abnormal regulation of hypoxia-inducible factor (HIF), which in turn leads to disorder of the body's physiological functions, including any disease in which a decrease in HIF level will bring beneficial effects. HIF-related diseases include, but are not limited to, tumor growth and metastasis, tumor drug resistance, diabetic nephropathy, etc. Detailed implementation mode

[0022] The following specific examples are used to further illustrate the present invention, but the present invention is by no means limited to these examples.

[0023] Example 1 HIF transcriptional inhibition activity test

[0024] (1) Activity test cell model: HCT 116 (human colon cancer cells) infected with lentiviral vector.

[0025] (2) Test method: Inoculate HCT116 cells into a 24-well plate and culture them in DMEM containing 10% FBS for 24 h. After the cells adhere, use the transfection reagent PEI to co-transfect the VEGF 5×HRE-Firefly Luciferase plasmid and the CMV-RenillaLuciferase plasmid into the cells. After 24 h of plasmid expression, add the compound of the present invention and treat it under hypoxic conditions (1% O2) for 24 h. Subsequently, lyse the cells with 1× cell lysis buffer and perform a Dual-Luciferase experiment using a Dual-Luciferase assay kit to detect the effect of the compound on HIF transcriptional activity.

[0026] (3) Calculate the inhibition rate according to the following formula: Inhibition rate = (1 - Luciferase value of the compound treatment group / Luciferase value of the hypoxic control group) × 100%

[0027] Test results:

[0028] Table 1 Effect of the compound of the present invention at 1 μM on inhibiting HIF transcription

[0029] Compound Inhibition rate (%) Compound Inhibition rate (%) 1 ++++ 4 ++++ 2 ++++ 5 ++++ 3 ++++ A -

[0030] Note: In the table, "++++" indicates that the inhibition rate ≥ 70%; "+++" indicates that the inhibition rate is 40 - 69%; "++" indicates that the inhibition rate is 20 - 39%; "+" indicates that the inhibition rate is 5 - 19%; "-" indicates that the inhibition rate is less than 5%.

[0031] Note: The compound A was tested in parallel in the present invention as a control.

[0032] Conclusion: Compared with compound A, compounds 1-5 of the present invention have stronger inhibitory activity on HIF transcriptional activity and can be used to treat diseases such as tumor growth and metastasis, tumor drug resistance, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), diabetic nephropathy, non-alcoholic fatty liver disease (NAFLD), cardiovascular diseases, and neurological diseases.

[0033] It should be noted that there are other ways to implement the present invention; accordingly, the embodiments of the present invention are illustrative, but not limited to the content described in the present invention, and may also be modifications made within the scope of the present invention or equivalent content added in the claims; all publications or patents cited in the present invention will be used as references for the present invention.

Claims

1. A terphenyl compound, characterized in that, Use of a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, especially as a HIF inhibitor, characterized in that the compound has the following structure: The specific structure is as follows:

2. A drug capable of treating and / or preventing diseases caused by hypoxia-inducible factor (HIF), characterized in that It contains the compound described in claim 1, or a stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof as an active ingredient.

3. Use of the drug described in claim 2 in the treatment and / or prevention of diseases related to hypoxia-inducible factor (HIF), said diseases including those HIF-related diseases such as tumor growth and metastasis, tumor drug resistance, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), diabetic nephropathy, non-alcoholic fatty liver disease (NAFLD), cardiovascular diseases, and neurological diseases.

Images