Substituted guanidyl-containing derivative and application thereof in preparation of osteoclast differentiation inhibitor

An osteoclast, differentiation inhibition technology, applied in bone diseases, organic chemistry, drug combination, etc., can solve problems such as high price, need for subcutaneous injection, and limited use

Active Publication Date: 2021-07-06
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although denosumab is considered to be a good example of osteoclast-targeted therapy at present, it requires subcutaneous injection and its high price limits its use

Method used

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  • Substituted guanidyl-containing derivative and application thereof in preparation of osteoclast differentiation inhibitor
  • Substituted guanidyl-containing derivative and application thereof in preparation of osteoclast differentiation inhibitor
  • Substituted guanidyl-containing derivative and application thereof in preparation of osteoclast differentiation inhibitor

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0042] Experimental example 1 Substituted guanidine derivatives Sephin1, Sen-01, Sen-04, Sen-06 inhibit RANKL-induced osteoclastogenesis or bone resorption in mice

[0043] Take the femur and tibia of C57BL / 6 mice, strip the muscle and cut off both ends, use a syringe to absorb α-MEM to repeatedly wash the bone marrow cavity of the femur and tibia, and flush out the bone marrow until the bone marrow cavity turns white, at 37°C, 5% CO 2 Adherent cells were taken after being placed in the incubator for 48 hours, and the cells were inoculated in 96-well plates. After that, different concentrations of drugs were added to the drug group, and the stimulator RANKL was added 2 hours later (the final concentration of RANKL was 50 ng / ml). 3-4 days after induction, carry out TRAP staining, observe and take pictures under a microscope, and count osteoclasts as TRAP-positive cells with more than 3 nuclei. The bone resorption plate was washed to remove cells on the 7th day of induction, obs...

experiment example 2

[0045] Experimental Example 2 Substituted Guanidyl Derivative Sephin1 Improves Bone Density in Ovariectomized (OVX) Mice Osteoporosis Model in Vivo

[0046] Fifteen C57BL / 6 female mice aged 8 weeks, negative control group (sham) were 5 mice in sham operation group, and the remaining 10 OVX model mice were randomly divided into positive control group (ovx), drug group Sephin1 group (ovx +Sephin1 (4mg / kg)), 5 rats in each group. The negative control group and the positive control group were injected with normal saline; in the drug intervention group, 4 mg / kg of Sephin1 was injected intraperitoneally, and the drug was injected intraperitoneally the next day. All mice were continuously injected intraperitoneally for 6 weeks. Reserved in formalin.

[0047] Through Micro-CT scanning, it was found that compared with the negative control group, the bone mass of the mice in the OVX model group was significantly reduced, while the Sephin1 intervention group significantly increased the ...

experiment example 3

[0049] Experimental example 3 Substituted guanidine derivative Sephin1 inhibits osteoclast differentiation and bone activity in patients with osteoporosis

[0050] Lymphocytes were isolated from the peripheral blood of patients with osteoporosis, and CD14 magnetic beads were used to sort the lymphocytes, and the obtained cells were inoculated on artificial bone sheets coated with The Osteo Assay was cultured in 96-well plates, and drugs of different concentrations were added to the drug group, and the stimulator RANKL was added after 2 hours (the final concentration of RANKL was 5ng / ml). Observe and take pictures, and count osteoclasts as TRAP-positive cells with more than 3 nuclei. The bone resorption plate was changed every three days, and the cells were washed away after 7 days of induction, observed and photographed under a 40×Nikon inverted optical microscope, and the percentage of bone resorption area in each well was calculated by Image-Pro Plus software.

[0051] The...

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Abstract

The invention discloses an application of a substituted guanidyl-containing derivative in preparation of an osteoclast differentiation inhibitor. The substituted guanidyl-containing derivative has a direct and remarkable inhibition effect on RANKL-induced osteoclast differentiation and bone resorption activity, so that the substituted guanidyl-containing derivative can be used as an osteoclast differentiation inhibitor drug for treating diseases treated by an osteoclast differentiation inhibitor.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a substituted guanidino derivative and its new application. Background technique [0002] Osteoclasts (OCs) are the only cells responsible for bone resorption in the body. Factors such as estrogen deficiency and elevated inflammatory factors will increase the level of RANKL in the body, causing highly activated osteoclasts. ) interacts with extracellular matrix proteins and tightly attaches to the bone surface. Then the proton pump at the folded boundary of osteoclasts will generate an acidic environment, and under the action of matrix enzymes synthesized by osteoclasts, calcium is easily dissolved from the bone. Therefore, when the bone resorption function of osteoclasts is dominant, it is easy to cause the increase of organic bone matrix resorption, and then lead to the occurrence and development of osteolytic diseases. Osteolytic bone destruction diseases mainly include osteoporosis (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C281/18C07D471/04C07D209/08C07D307/79C07D333/54C07C391/02A61P19/10A61P19/02A61P19/08A61P35/00
CPCC07C281/18C07D471/04C07D209/08C07D307/79C07D333/54C07C391/02A61P19/10A61P19/02A61P19/08A61P35/00
Inventor 李晓娟丁宗保王祎媛
Owner SOUTHERN MEDICAL UNIVERSITY
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