Tricyclic small-molecule inhibitor for macrophage movement inhibiting factor and application of tricyclic small-molecule inhibitor

A technology of small molecule inhibitors and movement inhibition, which is applied in anti-inflammatory agents, organic active ingredients, non-central analgesics, etc., and can solve the problems of successful marketing of small molecule inhibitors of MIF and low activity

Inactive Publication Date: 2016-04-13
范国煌
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the small-molecule inhibitors of MIF discovered so far are generally less active, and no small-molecule inhibitors targeting MIF have been successfully marketed so far.

Method used

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  • Tricyclic small-molecule inhibitor for macrophage movement inhibiting factor and application of tricyclic small-molecule inhibitor
  • Tricyclic small-molecule inhibitor for macrophage movement inhibiting factor and application of tricyclic small-molecule inhibitor
  • Tricyclic small-molecule inhibitor for macrophage movement inhibiting factor and application of tricyclic small-molecule inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The analysis of the inhibitory effect of FGH-1001 on pancreatic cancer cell proliferation and tumor formation in this example is as follows:

[0038]MIF is highly expressed in various solid tumors such as pancreatic cancer, breast cancer, non-small cell lung cancer, and colon cancer. A large number of studies have shown that the expression level of MIF is closely related to the occurrence and development of the above tumors.

[0039] We first observed the effect of FGH-1001 on the apoptosis of pancreatic cancer cells PANC-1. see Image 6 As shown, different concentrations of FGH-1001 and pancreatic cancer cell line PANC-1 cells (5x10 6 ) were incubated for different times to observe the morphology of the cells under a light microscope. The results showed that FGH-1001 significantly promoted the apoptosis of PANC-1 cells.

[0040] We further observed the effect of FGH-1001 on tumor cell colony formation. see Figure 7 As shown, different concentrations of FGH-1001 ...

Embodiment 2

[0043] Inhibitory effect of FGH-1001 in this example on LPS-induced inflammation.

[0044] Studies have shown that MIF participates in the inflammatory process by causing macrophages to polarize in the M1 (inflammatory) direction by inhibiting pathways such as glucocorticoids. In this experiment, the effect of FGH-1001 on LPS-induced inflammatory response was observed. Six-week-old male C57 mice were randomly divided into two groups, with 10 mice in each group. They were given solvent (control group) or FGH-1001 (50 mg / kg, b.i.d.) by intragastric administration, and then intraperitoneally injected 100 μl LPS (10 ng / ml ), then the peritoneal macrophages were collected under deep phenobarbital anesthesia, the levels of cytokines were detected by suspension chip technology (Luminex) and the gene expression levels related to M2 macrophages were detected by Real-time PCR technology. The results showed that FGH-1001 significantly inhibited the production of inflammatory cytokines (...

Embodiment 3

[0046] Inhibitory effect of FGH-1001 in this example on brain tissue damage after ischemic stroke.

[0047] Studies have shown that MIF is highly expressed in the lesions of patients with atherosclerosis, and gene silencing of MIF significantly inhibits brain tissue damage after stroke. Our experiments investigated the effects of FGH-1001 on brain tissue damage in a rat model of stroke (MCAO). Eight-week-old male rats were randomly divided into two groups, 10 in each group, and a stroke model of middle cerebral artery occlusion (MCAO) was constructed respectively. Three weeks after the operation, the solvent (control group) or FGH-1001 (50mg / kg, b.i.d.) was given by intragastric administration, and the brain was decapitated, frozen section (10 μm), immunohistochemical staining (A) was performed with GFAP antibody, and the damage area was calculated , for statistical analysis (B). The results showed that FGH-1001 significantly inhibited the damage of brain tissue in MCAO rats...

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Abstract

The invention discloses a tricyclic small-molecule inhibitor for a macrophage movement inhibiting factor (MIF). The molecular structure formula of the tricyclic small-molecule inhibitor is shown in the specification, wherein R1, R2, R3 and R4 are independently selected from combinations including hydrogen, halogen, C1-C3 alkyl, alkyl groups, aryl, aralkyl groups, a naphthenic base, a heterocyclic ring and halogen-substituted alkyl, R5, R6 and R8 are independently selected from combinations including sulfenyl, an oxygen base, a nitrogen base, alkyl groups, aryl and aralkyl groups, and R 7 is independently selected from combinations including hydroxyl, halogen, alkyl groups, aryl, aryloxy, aralkyl groups, a naphthenic base, a heterocyclic ring, halogen-substituted alkyl and the like. The tricyclic small-molecule inhibitor for the MIF can be used for treating various diseases caused by expression or activity rising of the MIF.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a tricyclic small molecule inhibitor of macrophage migration inhibitory factor (MIF), in particular to a tautomerase activity of MIF and the inflammation and cell proliferation that MIF receives. Inhibitory small molecule compounds. Background technique [0002] Macrophage migration inhibitory factor (MIF) is a protein containing 115 amino acid residues, with a molecular weight of 12.5kDa, and a three-dimensional structure composed of α chain and β chain. The protein crystal structure of MIF is a homotrimer, each monomer has two parallel α-helices and 6 β-strands. [0003] One of the important sources of MIF is the pituitary gland, accounting for 0.05% of the total pituitary protein. Monocytes / macrophages are also one of the important sources of MIF. In addition, lymphocytes also express MIF. MIF can play a role by combining with the extracellular group of the cell membrane surface p...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D401/14C07D409/14C07D405/14C07D413/14C07D249/12C07D409/04A61K31/4196A61K31/4439A61K31/4709A61K31/497A61P9/10A61P13/12A61P29/00A61P19/02A61P37/02A61P37/08A61P35/00A61P25/28A61P3/10
CPCC07D403/04C07D249/12C07D401/14C07D405/14C07D409/04C07D409/14C07D413/14
Inventor 范国煌
Owner 范国煌
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