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PD-L1 cyclopeptide inhibitor containing hydrazide structure

A technology of solvates and tautomers, applied in the field of cyclic peptide compounds, can solve the problem of not being able to block the interaction of PD-1, and achieve good pharmacokinetic characteristics, tumor cell growth inhibition, and a suitable half-life. Effect

Pending Publication Date: 2021-12-07
NANJING LEEWE BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of compound can selectively interfere with the binding of PD-L1 to PD-1 and CD80 to bind itself to PD-L1, but it cannot block the interaction of PD-1 / PD-L2 or CD80 / CTLA4

Method used

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  • PD-L1 cyclopeptide inhibitor containing hydrazide structure
  • PD-L1 cyclopeptide inhibitor containing hydrazide structure
  • PD-L1 cyclopeptide inhibitor containing hydrazide structure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] The preparation of embodiment 1 compound I-1

[0066] 1) Synthesis of fragment 1-T1 resin

[0067] Weigh 50g of Rink Amino MBHAResin with a substitution degree of 0.324mmol / g, add 500mL of DCM, bubble nitrogen, swell for 30min, and remove the solvent by suction filtration. DCM (150 mL*3) was added to wash the filter cake. Add 400mL of 20% Pip / DMF (DMF:Pip; 80:20, volume ratio) solution and mix, stir for 5 minutes, and filter cake with suction; then add 400mL of 20% Pip / DMF solution, stir for 15 minutes, and filter with suction. The filter cake was washed successively with appropriate amount of DMF and DCM and sucked dry. 200 mL of a DCM solution containing 9.84 g of phenyl p-nitrochloroformate was added to the bottle. Under the conditions of nitrogen bubbling and stirring, 12.60 g of DIEA was added dropwise, and the mixture was stirred until the ninhydrin detection method monitored the reaction to be complete. Filter and drain. The filter cake was washed successive...

Embodiment 7

[0093] Example 7. The inhibitory activity of the compound of the present invention on PD-1 / PD-L1 protein-protein interaction Evaluation of these effects shows that the compound of the present invention has a significant inhibitory effect on PD1 / PD-L1.

[0094] The specific test method is as follows:

[0095] Experiment purpose and principle

[0096] HTRF (Homogeneous Times-Resolved Fluorescence) is a technique used to detect analytes in pure liquid phase systems. This technology is based on the two major technologies of fluorescence resonance energy transfer (FRET, Fluorescence Resonance Energy Transfer) and time-resolved fluorescence (TRF, Time-Resolved Fluorescence), opening a high-throughput drug screening tool.

[0097] Experimental Materials and Instruments

[0098] The HTRF kit was purchased from Cisbio (CAT#63ADK000CPAPEG), which contains Anti-Tag1-Cyptate, Anti-Tag2-XL665 / d2, Tag1-PD-L1, Tag2-PD-1, Dilution Buffer, Detection Buffer and other reagents required for exp...

Embodiment 8

[0111] Embodiment 8. Pharmacokinetic experiment

[0112] Experimental materials for the pharmacokinetic study of compound PD-1 in SD rats given to compound I-1 by single intravenous injection or subcutaneous injection

[0113] SD rats, half male and half male, SPF grade.

[0114] Test article preparation

[0115] For intravenous injection and subcutaneous injection, use 5% DMSO + 10% Solutol + 85% sterile water for injection;

[0116] Experimental groupings Compound I-1 of the present invention was administered in groups according to the following administration methods of groups 1-5, as shown in the following table.

[0117]

[0118] Method of administration

[0119] Weigh before administration, and calculate the dosage according to body weight. It is administered intravenously and subcutaneously.

[0120] Blood collection time point

[0121] IV: Before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration. PO: before administration, 15min...

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Abstract

The invention relates to a macrocyclic peptide compound containing a hydrazide structure, a racemate, a stereoisomer, a tautomer, an isotope label, a nitrogen oxide, a solvate, a polymorphic substance, a metabolite, an ester, a prodrug or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the macrocyclic peptide compound, and medical application of the macrocyclic peptide compound. The macrocyclic peptide compound has remarkable inhibitory activity on PD-1 / PD-L1 protein-protein interaction, and the inhibitory activity of some compounds on PD-1 / PD-L1 interaction is remarkably superior to that of positive control drugs.

Description

technical field [0001] The invention relates to cyclic peptide compounds, which are used as immunomodulators in treatment, and in particular to a PD-L1 cyclic peptide inhibitor containing a hydrazide structure. Background technique [0002] Programmed cell death protein 1 (programmed cell death protein, PD-1, also known as PDCD1 and CD279), is a type I transmembrane protein composed of 288 amino acid residues encoded by the gene PDCD1, and belongs to the B7-CD28 receptor superfamily member . Its structure includes four parts: immunoglobulin variable region (IgV), transmembrane region, immunoreceptor tyrosine inhibition motif, and immunoreceptor tyrosine conversion motif. Its expression in myeloid cells, dendritic cells, natural killer cells, monocytes, CD4 - CD8 - It is expressed on the surface of various immune cells such as thymocytes, regulatory T cells, B cells, and antigen-presenting cells. PD-1 has two ligands, PD-L1 (CD274) and PD-L2 (CD273), which are type I tran...

Claims

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Application Information

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IPC IPC(8): C07K7/56A61K38/12A61P35/00A61P35/02A61P35/04A61P31/00A61P37/02
CPCC07K7/56A61P35/00A61P35/02A61P35/04A61P31/00A61P37/02A61K38/00A61K38/12
Inventor 宋志春杨凯徐萧和刘希蔡涛杨杰孙井龙候蓓邹正才
Owner NANJING LEEWE BIOPHARMACEUTICAL CO LTD
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