Methods and compositions for drugs to treat ophthalmic diseases
A technology of pharmacy and compounds, applied in metabolic diseases, drug combinations, sensory diseases, etc., can solve the problems of no phenotype and no immunodeficiency in mice
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[0123] Development of novel small molecule inhibitor compounds
[0124] Computational modeling of the crystal structure of STO-609 / CaMKK2 was used to develop small molecule inhibitors of CaMMK2 (SMIC) based on computational chemistry. In particular, the crystal structure of STO-609 / CaMKK2 was obtained, modifying part of the tool compound, which was not expected to interfere with receptor binding, but should have improved solubility (calculated LogP ~ 3), whereas cell penetration No adverse effects (total polar surface area < 140 considered favorable). Five (5) starting compounds were synthesized by MonomerChem (RTP, NC) and used to generate the data in this paper.
[0125] Table 1 below illustrates the five compounds initially synthesized, each representing a new subclass.
[0126] Table 1
[0127] Compound 1-10
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example 2
[0132] Biochemical activity against CaMKK2
[0133] Initial screening of compounds EY301-EY305 was performed in vitro in HEK293 cells (both tested at 10 μΜ). Briefly, HEK293 cells were cultured to subconfluence in RPMI-40 complete medium and 1% fetal bovine serum (FBS) at 37 °C in 5% CO 2 incubate. Cultured cells were then switched to serum-free medium overnight before starting the experiment. Cells were then pretreated with one of five SMICs (EY301, EY302, EY303, EY304, and EY305, all at a concentration of 10 μM), STO-609 (10 μM), or vehicle control at 37°C and incubated at 5 %CO 2 Incubate for 2 hours. Cells were then stimulated with the calcium ionophore ionomycin (0.5 mg / mL) for 15 min and then washed, harvested and lysed to recover total protein using standard methods. After standard protein gel electrophoresis, phospho-CaMKK2 ( Figure 4A ) or phospho-AMPK ( Figure 4B ) for western blotting. Studies were performed in triplicate. Densitometry analysis revealed t...
example 3
[0135] Functional screening of compounds 1-5
[0136] One-way mixed lymphocyte reaction (MLR) ( Figure 5 ) will be used to screen the functional inhibition ability of EY301-EY305. Spleen cells from C57BL / 6 mice were used as responder cells, and spleen cells from BALB / c mice (irradiated with Co60, 3000 rads) were used as stimulator cells. The two types of cells were then mixed in the same volume and concentration and incubated at 37°C in low serum conditions in 5% CO 2Incubate for 24 hours. Methods were 1) vehicle control; 2-6) one of five SMICs (EY301-EY305), or 7) STO-609 (concentrations of 10 μM, 3 μM, 1 μM, 0.3 μM and 0.1 μM). Each concentration / condition will be replicated three times. The supernatant was then recovered and concentrated for analysis by enzyme-linked immunosorbent assay (ELISA) for several major T-cell and macrophage-derived cytokines and effector molecules that are thought to pass through the infiltrated immune system. cells to mediate destructive i...
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