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Novel compounds activating the nrf2 pathway

A compound and peptide compound technology, applied in the field of oxidative stress-dependent pathology, can solve the problem that peptides do not easily pass through cell membranes

Pending Publication Date: 2020-04-10
ALMIRALL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, it has been found that peptides containing the DXETGE sequence do not readily cross cell membranes

Method used

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  • Novel compounds activating the nrf2 pathway
  • Novel compounds activating the nrf2 pathway
  • Novel compounds activating the nrf2 pathway

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0755] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or racemate resolution using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemate precursor) can be combined with a suitable optically active compound such as an alcohol, or, where the mixture contains acidic or basic moieties, an acid or base such as tartaric acid or 1-phenylethylamine) reacted. The resulting diastereomeric mixtures may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted into the corresponding pure enantiomers by methods well known to those skilled in the art. The chiral compounds of the present invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography (usually HPLC) on asymmetric resins using a mobile phase consisting of a hydrocarbon (usually...

Embodiment

[0831] A specific embodiment of the invention is represented by the following sequence:

[0832] Peptide List (SEQ ID NO)

[0833] H-Leu-Gln-Trp (indol-2-yl-& 1 )-Asp-Glu-Glu-Thr-Gly-Glu-Cys(& 1 )-Leu-Pro-OH (SEQ ID NO: 1)

[0834] {[H-Leu-Gln-Cys(& 1 )-Asp-Glu-Glu-Thr-Gly-Glu-Cys(& 2 )-Leu-Pro-OH][& 1 (1,4-Phenylenediyl) dimethylene & 2 ]} (SEQ ID NO: 2)

[0835] {[H-Leu-Gln-Cys(& 1 )-Asp-Glu-Glu-Thr-Gly-Glu-Cys(& 2 )-Leu-Pro-OH][& 1 (1,3-Phenylenediyl) dimethylene & 2 ]} (SEQ ID NO: 3)

[0836] {[& 1 Leu-Gln-Cys (& 2 )-Asp-Glu-Glu-Thr-Gly-Glu-Cys(& 3 )-Leu-Pro& 1 ][& 2 (1,3-Phenylenediyl) dimethylene & 3 ]} (SEQ ID NO: 4)

[0837] {[& 1 Leu-Gln-Cys (& 2)-Asp-Glu-Glu-Thr-Gly-Glu-Cys(& 3 )-Leu-Pro& 1 ][& 2 (1,4-Phenylenediyl) dimethylene & 3 ]} (SEQ ID NO: 5)

[0838] {[Acetyl-Cys(& 1 )-Asp-Glu-Glu-Thr-Gly-Glu-Cys(& 2 )-NH 2 ][& 1 (1,3-Phenylenediyl) dimethylene & 2 ]} (SEQ ID NO: 6)

[0839] Acetyl-Trp (indol-2-yl-& 1 )-Asp-Glu-Glu-Thr-Gly-Glu-...

preparation example 17

[1037] From tetrahydro-2H-pyran-4,4-diyl)bis(hydroxymethylene) (according to US2010 / 0099688 Preparation 17 from tetrahydro-2H-pyran-4,4-dicarboxy Preparation of tetrahydro-2H-pyran-4,4-diyl)bis(methylene)bis(triflate).

[1038] 1- Analysis method

[1039] Analytical RP-HPLC

[1040] Analytical RP-HPLC was performed on a Waters instrument comprising a separation module (Waters 2695), an autoinjector (Waters 717 autosampler), a photodiode array detector (Waters 2998) and a software system controller (Empower). UV detection was performed at 220 nm and a linear gradient of eluent B (ACN + 0.036% TFA) to A (water + 0.045% TFA) was run at a flow rate of 1.0 mL / min for 8 minutes.

[1041] By indicating the change from eluent B to eluent A, the retention time (t R ) analytical RP-HPLC gradient (Table 2).

[1042] Example using the gradient of column 1, Gradient (%B) = 0-100:

[1043] time (minute) minute) Eluent A(%) Eluent B(%) 0 100 0 8 0 100

...

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Abstract

The invention relates to peptide compounds, which peptide compounds are compounds of formula (I)', or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer thereof: (I)', whereinR1; R2; s; t; u; Aa78 and G1 are as defined herein. The peptide compounds are useful in activating the Nrf2 pathway.

Description

technical field [0001] The present invention relates to novel peptides that activate the Nrf2 pathway and their use in oxidative stress-dependent pathologies. Background technique [0002] Oxidative stress is caused by an imbalance between reactive oxygen species (ROS) present in living systems and the system's ability to remove them or repair the damage caused. ROS are also required for the body's immune system to kill pathogens. Under normal conditions, the amount of ROS is kept within certain limits. When these limits are exceeded, some diseases can occur in the body. Oxidative stress is associated with the development of several conditions such as Parkinson's disease, depression, Alzheimer's disease, atherosclerosis, heart failure, myocardial infarction, diabetes, cancer, COPD, exacerbation of COPD, acute lung injury, radiation-induced dermatitis, chemical-induced dermatitis, contact-induced dermatitis, epidermolysis bullosa simplex, pachyonychia congenita, Hailey-Hai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08A61K38/00C07K14/47
CPCA61K38/00C07K7/08C07K7/64
Inventor 卡洛斯·皮格杜兰费尔南多·阿尔贝里奥帕洛梅拉米里亚姆·贡哥拉贝尼特斯马尔塔·帕拉迪丝巴斯莱亚·米雷特卡萨尔斯伊凡·拉莫斯托迷利罗史蒂芬·菲亚科安得烈·戴维斯斯特凡·格什温纳奥玛尔·布伦库伯卡洛斯·赫拉斯帕尼亚瓜努里亚·特拉莱罗卡内拉
Owner ALMIRALL