116175-22-5Relevant articles and documents
Molecular hybridization used to design and synthesize neo-tanshinlactone derivatives as PD-1/PD-L1 inhibitors
Lee, Kuo-Hsiung,Liu, Jianmin,Morris-Natschke, Susan,Wang, Ping,Wang, Yue,Zhang, Menghan
, (2022/01/13)
Four series of molecular hybrids (37 final products) of neo-tanshinlactone, a natural product extracted from Salvia miltiorrhiza Bunge, and known PD-1/PD-L1 interaction inhibitors were prepared as possible chemotherapeutic agents against triple negative breast cancer. Screening using a homogenous time-resolved fluorescence method resulted in three lead compounds (MZ52 IC50 74 ± 4 nM; MZ58 IC50 134 ± 17 nM; MZ61 IC50 225 ± 19 nM). With less T cell cytotoxicity and effects in activating CD8+ T cells in a T cell proliferation assay and a functionality experiment, MZ58 was selected as the best candidate for animal experiments. MZ58 exhibited antitumor effects in a subcutaneous transplantation tumor model as well as effects in reducing T cell exhaustion. In conclusion, after in vivo and in vitro experiments, we successfully acquired an effective candidate (MZ58) showing antitumor effects with low cytotoxicity toward T cells as well as the ability to activate CD8+ T cells and reduce T cell exhaustion.
BENZYLAMINE DERIVATIVE, PREPARATION METHOD THEREFOR AND USE THEREOF
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Page/Page column 14-15, (2022/02/24)
The present invention relates to a benzylamine derivative, a preparation method therefor and use thereof, and in particular, to a benzylamine derivative as represented by general formula (I), or a pharmaceutically acceptable stereoisomer, salt, solvate, or prodrug thereof, which has a strong binding capability with human PD-L1, can obviously inhibit the interaction of PD-1/PD-L1, and has significant anti-tumor efficacy in vivo. Therefore, the present invention also relates to a preparation method for the benzylamine derivative and use thereof in preparing a drug for treating PD-1/PD-L1-related diseases.
Design, Synthesis, and Evaluation of o-(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy in Vivo
Ouyang, Yiqiang,Gao, Jian,Zhao, Lei,Lu, Junfeng,Zhong, Haiqing,Tang, Hua,Jin, Shuanglong,Yue, Lu,Li, Yuezhen,Guo, Wenjie,Xu, Qiang,Lai, Yisheng
, p. 7646 - 7666 (2021/06/28)
Two series of novel o-(biphenyl-3-ylmethoxy)nitrophenyl compounds (A1-31 and B1-17) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC50 values ranging from 2.7 to 87.4 nM except compound A17, and compound B2 displayed the best activity. Further experiments showed that B2 bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, B2 significantly promoted interferon-gamma secretion in a dose-dependent manner in vitro and in vivo. Especially, B2 exhibited potent in vivo anticancer efficacy in an LLC-bearing allograft mouse model at a low dose of 5 mg/kg, which was more active than BMS-1018 (tumor growth inhibition rate: 48.5% vs 17.8%). A panel of immunohistochemistry and flow cytometry assays demonstrated that B2 effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that B2 is a promising PD-1/PD-L1 inhibitor worthy of further development.
Nitrophenyl ether compounds, and preparation methods, pharmaceutical compositions and application thereof
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Paragraph 0077-0081, (2020/06/09)
The invention discloses nitrophenyl ether compounds, and preparation methods, pharmaceutical compositions and application thereof, belonging to the field of medicines. The invention particularly relates to the nitrophenyl ether compounds with structural c
Biphenyl compound as well as preparation method and medical application thereof
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Paragraph 0342-0348, (2020/11/22)
The invention discloses a biphenyl compound as well as a preparation method and medical application thereof, the structure of the biphenyl compound is shown as a formula (I) or a formula (II), and thebiphenyl compound or pharmaceutically acceptable salt, tautomer, meso-isomer, raceme, stereoisomer, metabolite, metabolite precursor, prodrug or solvate thereof is a PD-L1 inhibitor. The compound hasa remarkable inhibiting effect on the interaction of PD-1 and PD-L1 protein, so that the compound can be applied to the preparation of PD-L1 inhibitors and immunomodulator drugs for preventing or treating tumors, autoimmune diseases, organ transplant rejection, infectious diseases and inflammatory diseases.
Design, synthesis and biological evaluation of 2-methyl-(1,1′-biphenyl)-pyrimidine conjugates
Chen, An,Narva, Suresh,Shi, Jia,Wu, Dong-Liang,Wu, Yan-Ling,Zhang, Wen,Zhao, Xiao-Yin
supporting information, (2020/07/02)
Small molecule inhibitors of biphenyl structure as core backbone have shown a significant effect on PD-1/PD-L1 axis, and 2-amino-pyrimidine structure is a promising privileged scaffold in medicinal chemistry and drug discovery. We designed by combination principles and synthesized 27 novel compounds with N-((2-methyl-[1,1′-biphenyl]-3-yl)methyl)pyrimidin-2-amine as a basic skeletal structure, and their anti-cancer activity was evaluated. Among compounds, 15a-d and 16b displayed strong anti-cancer effects on 9 tested cancer cell lines, in particular, the 16b did the highest inhibitive activity, but against HepG2 cells, and possessed the lowest IC50 value of 2.08 μΜ towards HT-29 cells.
Biphenyl-pyrimidine conjugate as well as preparation method and application thereof
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Paragraph 0080; 0084, (2020/08/30)
The invention discloses a biphenyl-pyrimidine conjugate as well as a preparation method and application thereof. The structural general formula of the biphenyl-pyrimidine conjugate is shown as a formula (I) (See the specification), wherein R1 is selected from H, halogen, C1-C3 fluoroalkyl, morpholinyl, piperazinyl, pyrrolidinyl or dimethylamino, and R2 is selected from halogen, dimethylamino, diethylamino, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, N-(3-dimethylamino) propyl, N-(3-diethylamino) propyl, N-(1-(3-aminopropyl) pyrrolidinyl), N-(1-(3-aminopropyl) piperidinyl) or N-(1-(3-aminopropyl) morpholinyl). Through homogeneous time-resolved fluorescence experiments, it is found that the compound provided by the invention can inhibit the interaction of PD-1/PD-L1 and restore theactivity of T cells, so that the compound has an anti-tumor effect. The invention provides important reference value for discovery of new anti-tumor small molecule drugs, especially for promotion of research and development of biphenyl-pyrimidine conjugate targeted PD-1/PD-L1 clinical drugs.
Design, Synthesis, and Biological Evaluation of Linear Aliphatic Amine-Linked Triaryl Derivatives as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction with Promising Antitumor Effects in Vivo
Guo, Jialin,Luo, Longlong,Wang, Zhihong,Hu, Naijing,Wang, Wei,Xie, Fei,Liang, Erguang,Yan, Xinlin,Xiao, Junhai,Li, Song
, p. 13825 - 13850 (2020/12/01)
A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound 58 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC50 value of 12 nM and a KD value of 16.2 pM, showing a binding potency approximately 2000-fold that of hPD-1. Compound 58 could bind with hPD-L1 on the cellular surface and competitively block the interaction of hPD-1 with hPD-L1. In a T cell function assay, 58 restored the T cell function, leading to increased IFN-γsecretion. Moreover, in a humanized mouse model, compound 58 significantly inhibited tumor growth without obvious toxicity and showed moderate PK properties after intravenous injection. These results indicated that 58 is a promising lead for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.
Pomalidomide derivative and application thereof
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Paragraph 0058-0060, (2020/07/13)
The invention relates to a pomalidomide derivative. The chemical structure of the pomalidomide derivative is shown as the following formula (I), in the formula (I), R1 is phenyl or 1, 4-benzodioxane,R2 is chlorine or bromine, R3 is hydrogen or a 3-methylbenzonitrile group, and X is a linking group selected from ethylenediamine, propane diamine, butanediamine, pentanediamine, hexamethylenediamine,piperazine succinic acid, piperazine glutaric acid, piperazine diglycolic acid, ethylenediamine succinic acid, ethylenediamine glutaric acid, ethylenediamine diglycolic acid, propane diamine glutaricacid, butanediamine glutaric acid or pentanediamine malonic acid. The pomalidomide derivative disclosed by the invention can inhibit the mutual combination of a programmed cell death receptor 1/a programmed cell death ligand 1 (PD-1/PD-L1), can be used for preparing a PD-1/PD-L1 inhibitor, and has a remarkable effect.
Fused ring compound and application thereof (by machine translation)
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, (2019/10/01)
The invention discloses a fused ring compound and application. The invention provides a compound, a pharmaceutically acceptable salt, a hydrate, a solvate, a metabolite, a stereoisomer, a tautomer or a prodrug. The compound I, provided by the invention, has the advantages of high activity, high bioavailability, stable medicine, oral administration, and the like. (by machine translation)
