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Angiotensin converting enzyme 2 inhibitor, application thereof and anti-coronavirus infection medicine

An angiotensin, coronavirus technology, applied in the field of angiotensin converting enzyme 2 inhibitors, anti-coronavirus infection drugs, can solve the problem of poor activity and pharmacokinetic properties, restricted use, immunogenicity, oral biological Poor utilization, etc.

Active Publication Date: 2022-01-11
SHENZHEN INNOVATION CENT OF SMALL MOLECULE DRUG DISCOVERY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, several methods listed above are still in the stage of preclinical research
The use of protein and peptide biological products is limited in many ways, such as immunogenicity and poor oral bioavailability
In addition, the developed small molecule compound inhibitors have shortcomings such as poor activity and pharmacokinetic properties, which limit their use in vivo

Method used

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  • Angiotensin converting enzyme 2 inhibitor, application thereof and anti-coronavirus infection medicine
  • Angiotensin converting enzyme 2 inhibitor, application thereof and anti-coronavirus infection medicine
  • Angiotensin converting enzyme 2 inhibitor, application thereof and anti-coronavirus infection medicine

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0054] In some embodiments, the preparation method of angiotensin-converting enzyme 2 inhibitor comprises:

[0055] S01. Provide a solid phase carrier, amino acid substrate I and condensing agent. The amino terminal of amino acid substrate I is connected with an amino protecting group. Dissolve the solid phase carrier and amino acid substrate I in the reaction solvent, add the condensing agent, and then inert gas The reaction is carried out under the environment, so that the amino acid substrate I is immobilized on the solid phase support through the carboxyl terminal connection, and the first resin is obtained;

[0056] S02, removing the amino protecting group on the first resin to obtain the second resin;

[0057] S03. Taking the amino acid substrate I with the amino protecting group removed on the second resin as the synthesis starting point, refer to the operations of steps S01 and S02 to repeat the steps of condensation into peptides, washing, deprotection, and washing, a...

Embodiment 1

[0065] Compound I was synthesized in this example 1 : , including the following steps:

[0066] S11. Dissolve 2-CTC resin (0.10 mmol, 1.00 eq, Sub 1.10 mmol / g) and Fmoc-L-4-fluorophenylalanine (60.7 mg, 0.15 mmol, 1.50 eq) in 3 mL DCM, add dropwise DIEA (51.6 mg, 0.40 mmol, 0.066 mL, 4.00 eq), refluxed at room temperature for 2 h under nitrogen protection, added 0.5 mL of methanol, and filtered the reaction system after 30 min to obtain the first resin. In the first resin, Fmoc-L- 4-Fluorophenylalanine is immobilized on 2-CTC resin through carboxyl-terminal connection;

[0067] S12. Dissolve the first resin in a DMF solution (100 mL) containing 20% ​​piperidine, stir for 5 min under nitrogen protection, wash the resin with DMF (80 mL), and filter to obtain the second resin; compared to the first resin, the The L-4-fluorophenylalanine part on the second resin has taken off the protecting group Fmoc;

[0068] S13. Dissolve HBTU (108 mg, 0.285 mmol, 2.85 eq) and Fmoc-L-3-(3-...

Embodiment 2

[0076] Compound I was synthesized in this example 2 : , including the following steps:

[0077] S21. Dissolve 2-CTC resin (0.10 mmol, 1.00 eq, Sub 1.10 mmol / g) and Fmoc-D-phenylalanine (60.7 mg, 0.15 mmol, 1.50 eq) in 3 mL DCM, add dropwise DIEA ( 51.6 mg, 0.40 mmol, 0.066 mL, 4.00 eq), reflux at room temperature for 2 h under nitrogen protection, add 0.5 mL of methanol, filter the reaction system after 30 min to obtain the first resin, in the first resin, Fmoc-D-phenylbutylene The amino acid is immobilized on the 2-CTC resin through the carboxyl terminal connection;

[0078] S22. Dissolve the first resin in a DMF solution (100 mL) containing 20% ​​piperidine, stir for 5 min under nitrogen protection, wash the resin with DMF (80 mL), and filter to obtain the second resin; compared to the first resin, the The D-phenylalanine part on the second resin has taken off the protecting group Fmoc;

[0079] S23. Dissolve HBTU (108 mg, 0.285 mmol, 2.85 eq) and Fmoc-L-3-(3-benzothien...

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PUM

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Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to an angiotensin converting enzyme 2 inhibitor and application thereof and an anti-coronavirus infection. The angiotensin converting enzyme 2 inhibitor has the chemical structure shown in the general formula (I), R1 and R2 can be selected from hydrogen, halogen, amino, amido, hydroxyl, cyano, alkyl, naphthenic base and alkoxy, X is selected from hetero atoms such as N, O and S, and Y is selected from alkyl or acylamino. Through detection, the angiotensin converting enzyme 2 inhibitor has ACE2 inhibitory activity, can be used as a novel angiotensin converting enzyme 2 inhibitor, and has the potential of being applied to preparation of angiotensin converting enzyme 2 inhibitory drugs, especially anti-coronavirus infection drugs. (I).

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to an angiotensin-converting enzyme 2 inhibitor, an application thereof, and an anti-coronavirus infection drug. Background technique [0002] Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound glycoprotein, which is the main receptor for coronavirus and membrane binding, and participates in the specific binding and entry process of viruses and host cells. The interaction between the S protein of coronavirus and ACE2 is the initiation of its recognition and invasion of host cells, blocking the specific binding process of ACE2 and S protein can effectively prevent the invasion of coronavirus, and can be applied to the prevention and treatment of coronavirus. [0003] A variety of methods have been reported to block the recognition of ACE2 by the S protein and inhibit the invasion of host cells by coronaviruses: 1) Use small molecular compounds to target the ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/023C12N9/48A61K38/06A61P31/14
CPCC07K5/0202C12N9/485C12Y304/17023A61P31/14A61K38/00
Inventor 熊峰钟贞旻傅天成
Owner SHENZHEN INNOVATION CENT OF SMALL MOLECULE DRUG DISCOVERY CO LTD
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