Docosahexaenoic acid coupled prodrug of mTOR inhibitor PP242, preparation and application of docosahexaenoic acid coupled prodrug
A carbhexaenoic acid coupling, PP242-DHA technology, applied in the directions of drug combinations, pharmaceutical formulations, non-active ingredients medical preparations, etc., can solve problems such as the lack of PP242 anti-transplant rejection drugs, and achieve improved pharmacokinetics It has the advantages of scientific characteristics, convenient clinical transformation, and the effect of improving water solubility.
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Embodiment 1
[0043] Synthesis of PP242-DHA conjugated prodrugs, such as figure 1 Shown:
[0044] EDC (1-ethyl-(3-dimethylaminopropyl) carbodiimide, 25.6mg, 0.165mmol) and DMAP (4-dimethylaminopyridine, 20.2mg, 0.165mmol) were quickly added dropwise to the solution containing PP242 (46.2mg, 0.15mmol) and DHA (cis-4,7,10,13,16,19-docosahexaenoic acid, 52.5mg, 0.16mmol) reaction flask, add 2mL of anhydrous DMF to dissolve. Stir at 43°C for 6 hours, then remove the solvent, dilute the reaction mixture with dichloromethane, wash with 0.1M hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated saline solution respectively; dry the organic phase with anhydrous sodium sulfate, filter, and collect the filtrate The solvent was removed under reduced pressure; the product DHA-PP242 coupling prodrug (42.3 mg, yield 45.8%) (DHA-PP242) was obtained after separation and purification by column chromatography (DCM:MeOH=20:1).
[0045] The 1H NMR nuclear magnetic data of t...
Embodiment 2
[0048] 1) Preparation of PEGylated PP242-DHA nano-preparation:
[0049] The DHA-PP242 coupled prodrug prepared in Example 1 was dissolved in a dimethyl sulfoxide solvent containing DSPE-PEG2000 (the mass ratio of DHA-PP242 coupled prodrug to DSPE-PEG2000 was 10:1, two Methyl sulfoxide is the dissolved amount), and a mixed solution is obtained. Add water, the volume ratio of dimethyl sulfoxide to aqueous phase is 1:9, and remove the organic solvent by dialysis (MW 3500) to obtain a uniformly dispersed PEGylated PP242-DHA nano-preparation (DPNP or PEGylated NPs or PEGylated DPNP) . The particle size distribution and transmission electron microscopy as image 3 shown.
[0050] image 3 Among them, the preparation method of PP242-DHA self-assembled nanoparticles (Self-assembled DHA-PP242nanoparticles, or bare DPNP) is the same as the PEGylated PP242-DHA nano-preparation, the difference is that DSPE-PEG2000 is not added.
[0051] image 3 In A and B: "-" means nano-preparatio...
Embodiment 3
[0059] 1) Construction of allogeneic heterotopic heart transplantation model and immunosuppressive treatment experiment
[0060] Construct stable donor BALB / c to recipient C57BL / 6 mouse skin transplantation and mouse heterotopic heart transplantation model. The recipient's inferior vena cava anastomosis is constructed and obtained, and the allograft model has a strong and stable rejection effect, and is easy to observe and evaluate. After heart transplantation, it is administered once a day by intraperitoneal injection for a total of 10 days (40mg / kg / day). The weight change of the mice was recorded within 10 days after the administration, and the survival time of the heterotopic transplanted heart was used as the basis for evaluating the effect of the drug treatment.
[0061] Figure 5 In A, the heart of a Balb / c mouse was transplanted into the abdominal cavity of a C57BL / 6 mouse, and PP242 or pegylated DHA-PP242 nanoparticles (DPNP) were administered continuously for 10 day...
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