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PD-1/PD-L1 polypeptide inhibitor and medical application thereof

A technology of inhibitors and cyclic peptide compounds, applied in the field of medicinal chemistry, can solve the problem of slow progress of peptide inhibitors

Pending Publication Date: 2020-11-10
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with the research and development of monoclonal antibodies, the progress of peptide inhibitors in this field is slow

Method used

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  • PD-1/PD-L1 polypeptide inhibitor and medical application thereof
  • PD-1/PD-L1 polypeptide inhibitor and medical application thereof
  • PD-1/PD-L1 polypeptide inhibitor and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034]

[0035]According to the aforementioned "resin swelling step", after the resin is swollen, according to the "condensation step", the selected amino acids are respectively Fmoc-L-Gly-OH, Fmoc-L-Cys(Trt)-OH, Fmoc-L-Leu-OH, Fmoc-L-[N-Me]Nle-OH, Boc-L-Trp-OH, Fmoc-L-Trp(Boc)-OH, Fmoc-L-Dab(Boc)-OH, Fmoc-L-[O- tBu]Hyp-OH, Fmoc-L-Dap(Boc)-OH, Fmoc-L-Pro-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-[N-Me]Ala-OH, Fmoc -L-[O-tBu]Tyr-OH. After the condensation is completed, according to the aforementioned "peptide freeing step", select the corresponding amino acid to obtain the crude product of the linear peptide precursor. 60 mg of the crude product was dissolved in a total of 600 mL of acetonitrile:0.1M ammonium carbonate=1:1 (volume ratio), and the reaction was stirred at room temperature for 5 hours. The reaction solution was spin-dried and freeze-dried to obtain a powder mixture. The mixture was dissolved in acetonitrile: water = 1:1 (volume ratio), and the pure cyclic peptide precu...

Embodiment 2

[0037]

[0038] According to the method in the aforementioned "Example 1", t R = 27.251 min. HRESIMS:[M+H] + = 1916.9601.

Embodiment 3

[0040]

[0041] According to the synthesis of the aforementioned Example 1, the oxidation step was replaced by: taking 5 mg of the pure precursor and dissolving it in 500 μL of methanol:water=1:1 (volume ratio). 0.5 mg of potassium peroxymonosulfonate was added to the mixture, and stirred at room temperature. The reaction can be judged to be complete by RP-HPLC. Ascorbic acid was added to the reaction solution to destroy peroxide, and the product could be obtained according to the aforementioned "RP-HPLC separation step" after the reaction solution was freeze-dried. t R = 20.230 min. HRESIMS:[M+Na] + = 1896.9402.

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PUM

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Abstract

The invention discloses a cyclic peptide compound or a pharmaceutically acceptable salt, ester, solvates, prodrugs, racemate or isomers thereof, and a medical composition containing the compound as aneffective component. Experiments indicate the activity of the cyclic peptide compound or the pharmaceutically acceptable salt, ester, solvate, prodrugs, racemate or isomers thereof in inhibition of aPD1 / PDL1 pathway, and the invention also discloses an application of the compound to preparation of drugs for preventing and treating tumors taking the PD1 / PDL1 pathway as a target point. The tumorscomprise blood cancers, nervous system cancer, gastrointestinal cancer, esophageal cancer, urinary system cancer, lung cancer, liver cancer, skin cancer and the like.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a class of PD-1 / PD-L1 polypeptide compounds or pharmaceutically acceptable salts, esters or solvates thereof, and their use in the preparation of PD-1 / PD-L1 inhibitors Uses in medicine. Background technique [0002] PD-1, also known as CD279, is a type I transmembrane protein with a relative molecular weight of 55,000-60,000, which is a member of the immunoglobulin superfamily. Hydrophobic transmembrane and intracellular regions. The intracellular region includes C-terminal and N-terminal amino acid residues, and contains two independent phosphorylation sites, namely immunoreceptor tyrosine based inhibitory motif (ITIM) and immunoreceptor tyrosine Acid conversion motif (immunoreceptor tyrosine based switch motif, ITSM). PD-1 is mainly expressed on immune cells such as activated CD4+T cells, CD8+T cells, B cells, NK cells, monocytes and dendritic cells, an...

Claims

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Application Information

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IPC IPC(8): C07K7/08A61K38/12A61P35/00
CPCC07K7/08A61P35/00A61K38/00
Inventor 蒋晟周光飚郝海平苗琪吴筱星张阔军邱亚涛
Owner CHINA PHARM UNIV
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