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Tau protein visual PROTAC degradation compound as well as preparation method and application thereof

A compound and protein technology, applied in the field of Tau protein visualization PROTAC degradation compound and its preparation, can solve the problem of no retention of imaging function, and achieve the effect of strong degradation ability

Pending Publication Date: 2022-07-12
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Small molecule Tau protein degradation agent QC-01-175 as PET probe 18 The F-T807 backbone serves as the targeting ligand for Tau protein, but only retains the parent nucleus structure of the compound, and discards the radioactivity necessary for imaging 18 The F element, thus only retains the targeted binding ability of the PET probe to the Tau protein, but does not retain the imaging function

Method used

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  • Tau protein visual PROTAC degradation compound as well as preparation method and application thereof
  • Tau protein visual PROTAC degradation compound as well as preparation method and application thereof
  • Tau protein visual PROTAC degradation compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Example 1. Condensation of target carboxylic acid intermediate and linker / E3 ligand complex intermediate to obtain PROTAC final product molecule

[0117] Synthetic route of PROTACs using VHL ligand as E3 ligand

[0118]

[0119] (2R,4R)-1-((S)-2-(4-((2E,4E,6E)-2-cyano-7-(4-(dimethylamino)-2,6-dimethoxy Phenyl))hept-2,4,6-trienamido)butanamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5) -yl)benzyl)pyrrolidine-2-carboxamide D-11

[0120] The specific synthesis steps of D-11:

[0121] AD-4-5 (66.00 mg, 0.20 mmol) was dissolved in 7 mL of tetrahydrofuran, DIPEA (105.00 mg, 0.81 mmol) and DMAP (30.00 mg, 0.24 mmol) were added thereto under stirring, and the reaction solution was cooled to 0 °C After stirring for 10 min, HATU (155.00 mg, 0.41 mmol) was added, the temperature was naturally raised to room temperature, AD-L-V-3-2 (103.00 mg, 0.20 mmol) was added in batches after stirring for half an hour, and the mixture was stirred at room temperature for 12...

Embodiment 2

[0126] Example 2. Condensation of target carboxylic acid intermediate and linker / E3 ligand complex intermediate to obtain PROTAC final product molecule

[0127] Synthetic route of PROTACs using VHL ligand as E3 ligand

[0128]

[0129] (2R,4R)-1-((S)-2-(8-((2E,4E,6E)-2-cyano-7-(4-(dimethylamino)-2,6-dimethoxy phenyl))hept-2,4,6-trienamido)octamido)-3,3-dimethylbutyryl)-4-hydroxy-N-)4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide D-12;

[0130] The specific synthesis steps of D-12:

[0131] AD-4-5 (66.00 mg, 0.20 mmol) was dissolved in 7 mL of tetrahydrofuran, DIPEA (105.00 mg, 0.81 mmol) and DMAP (30.00 mg, 0.24 mmol) were added thereto under stirring, and the reaction solution was cooled to 0 °C After stirring for 10 minutes, HATU (155.00 mg, 0.41 mmol) was added, the temperature was naturally raised to room temperature, AD-L-V-2-2 (114.00 mg, 0.20 mmol) was added in batches after stirring for half an hour, and the mixture was stirred at room temperature for ...

Embodiment 3

[0137] Example 3. Condensation of target carboxylic acid intermediate and linker / E3 ligand complex intermediate to obtain PROTAC final product molecule

[0138] Synthetic route of PROTACs using pomalidomide as E3 ligand

[0139]

[0140] (2E,4E,6E)-2-cyano-7-(4-(dimethylamino)-2,6-dimethoxyphenyl)-N-(5-((2-(2,6- Dioxypiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)hept-2,4,6-trienamide D-16;

[0141] The specific synthesis steps of D-16:

[0142] Dissolve AD-4-5 (66.00 mg, 0.20 mmol) in 7 mL of tetrahydrofuran, add DIPEA (105.00 mg, 0.81 mmol) and DMAP (30.00 mg, 0.24 mmol) to it under stirring, and cool the reaction solution to 0 °C After stirring for 10 minutes, HATU (155.00 mg, 0.41 mmol) was added, the temperature was naturally raised to room temperature, AD-L-B-2-2 (71.00 mg, 0.20 mmol) was added in batches after stirring for half an hour, and the mixture was stirred at room temperature for 12 h. After monitoring the completion of the reaction, 14 mL of water ...

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Abstract

The invention provides a Tau protein visual PROTAC degradation compound and a preparation method and application thereof.The compound is obtained by condensing E3 ligase ligands with linker to prepare intermediates and connecting the intermediates with target probe molecules, in target selection, the selective binding effect of target small molecules and Tau protein is reserved, and in addition, the target probe molecules and the Tau protein can be combined, so that the target probe molecules can be combined with the target probe molecules, and the target probe molecules can be combined with the target probe molecules to obtain the Tau protein visual PROTAC degradation compound. The target compound is endowed with a brand new function of generating near-infrared fluorescence, so that the target compound can give play to the function of targeted degradation of Tau protein and can also emit detectable near-infrared fluorescence when the target compound is combined with Tau protein, and the degradation process of Tau protein is visualized; d-12 and D-16 both show fluorescence tendency similar to p-Tau reduction, visual design is achieved, the protein degradation process is expected to be more visually observed and regulated, and possibility is provided for combination of disease detection means and treatment means.

Description

Technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis and chemical engineering, and specifically relates to Tau protein visual PROTAC degradation compounds and their preparation methods and applications. Background technique [0002] Alzheimer’s disease (AD) is a neurodegenerative disease with an insidious onset and progressive development. It mainly manifests as cognitive dysfunction and has become one of the diseases with the fastest growing mortality rate in the world. However, most of the currently clinically approved drugs can only delay the progression of the disease and alleviate symptoms, but cannot effectively cure AD. Hypotheses about the cause of AD mainly include amyloid plaques, neurofibrillary tangles and intestinal microorganisms. Hyperphosphorylated Tau protein aggregates into insoluble neurofibrillary tangles, which damages biochemical communication inside and outside nerve cells. At the same time, It can also cause...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K1/13C07K1/02C07K1/22C07D401/04C09K11/06A61K38/05A61K31/454A61P25/28G01N21/64
CPCC07K5/06034C07D401/04C09K11/06A61P25/28G01N21/6428C09K2211/1029C09K2211/1007A61K38/00Y02P20/55
Inventor 马明亮李楚楚段燕红任梓玮王正阳
Owner EAST CHINA NORMAL UNIV
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