Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous-Crystalline Composites with a Polymer.

Article

作者: Markeev, Vladimir B ; Marakhova, Anna I ; Tishkov, Sergey V ; Vetcher, Alexandre A ; Parenago, Olga O ; Blynskaya, Evgenia V ; Alekseev, Konstantin V ; Vorobei, Anton M

N-butyl-N-methyl-1-phenylpyrrole[1,2-a] pyrazine-3-carboxamide (GML-3) is a potential candidate for combination drug therapy due to its anxiolytic and antidepressant activity. The anxiolytic activity of GML-3 is comparable to diazepam. The antidepressant activity of GML-3 is comparable to amitriptyline. GML-3 is an 18 kDa mitochondrial translocator protein (TSPO) ligand and is devoid of most of the side effects of diazepam, which makes the research on the creation of drugs based on it promising. However, its low water solubility and tendency to agglomerate prevented its release. This research aimed to study the effect of dry grinding, the rapid expansion of a supercritical solution (RESS), and the eutectic mixture (composite) of GML-3 with polyvinylpyrrolidone (PVP) on the particle size, dissolution rate, and lattice retention of GML-3. The use of supercritical CO₂ in the RESS method was promising in terms of particle size reduction, resulting in a reduction in the particle size of GML-3 to 20-40 nm with a 430-fold increase in dissolution rate. However, in addition to particle size reduction after RESS, GML-3 began to show signs of a polymorphism phenomenon, which was also studied in this article. It was found that coarse grinding reduced particle size by a factor of 2 but did not significantly affect solubility or crystal structure. Co-milling with the polymer made it possible to level the effect of the appearance of a residual electrostatic charge on the particles, as in the case of grinding, and the increased solubility in the resulting mechanical mixtures of GML-3 with the polymer may also indicate the dissolving properties of polymers (an increase in 400-800 times). The best result in terms of GML-3 solubility was demonstrated by the resulting GML-3:PVP composite at a ratio of 1:4, which made it possible to achieve a solubility of about 80% active pharmaceutical ingredient (API) within an hour with an increase in the dissolution rate by 1600 times. Thus, the creation of composites is the most effective method for improving the solubility of GML-3, superior to micronization.

2023-09-01·Molecular oncology

The LIN28B-let-7-PBK pathway is essential for group 3 medulloblastoma tumor growth and survival.

Article

作者: Kenney, Anna Marie ; Kumar, Sachin A ; Kunhiraman, Haritha ; Shahab, Shubin W ; Juraschka, Kyle ; Schniederjan, Matthew ; McSwain, Leon F ; Schnepp, Robert W ; MacDonald, Tobey J ; Saulnier, Olivier ; Roggeveen, Christianna M ; Taylor, Michael D ; Sun, Jiarong

Children with Group 3 medulloblastoma (G3 MB) have a very poor prognosis, and many do not survive beyond 5 years after diagnosis. A factor that may contribute to this is the lack of available targeted therapy. Expression of protein lin-28 homolog B (LIN28B), a regulator of developmental timing, is upregulated in several cancers, including G3 MB, and is associated with worse survival in this disease. Here, we investigate the role of the LIN28B pathway in G3 MB and demonstrate that the LIN28B-lethal-7 (let-7; a microRNA that is a tumor suppressor)-lymphokine-activated killer T-cell-originated protein kinase (PBK; also known as PDZ-binding kinase) axis promotes G3 MB proliferation. LIN28B knockdown in G3-MB-patient-derived cell lines leads to a significant reduction in cell viability and proliferation in vitro and in prolonged survival of mice with orthotopic tumors. The LIN28 inhibitor N-methyl-N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide (1632) significantly reduces G3 MB cell growth and demonstrates efficacy in reducing tumor growth in mouse xenograft models. Inhibiting PBK using HI-TOPK-032 also results in a significant reduction in G3 MB cell viability and proliferation. Together, these results highlight a critical role for the LIN28B-let-7-PBK pathway in G3 MB and provide preliminary preclinical results for drugs targeting this pathway.

2023-07-30·International journal of molecular sciences

Composites of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide with Polymers: Effect of Crystallinity on Solubility and Stability.

Article

作者: Markeev, Vladimir B ; Shishonin, Alexander Y ; Alekseev, Konstantin V ; Marakhova, Anna I ; Blynskaya, Evgenia V ; Vetcher, Alexandre A ; Tishkov, Sergey V

This work aimed to develop and characterize a water-soluble, high-release active pharmaceutical ingredient (API) composite based on the practically water-insoluble API N-butyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide (GML-3), a substance with antidepressant and anxiolytic action. This allows to ensure the bioavailability of the medicinal product of combined action. Composites obtained by the method of creating amorphous solid dispersions, where polyvinylpyrrolidone (PVP) or Soluplus^® was used as a polymer, were studied for crystallinity, stability and the release of API from the composite into purified water. The resulting differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and dissolution test data indicate that the resulting composites are amorphous at 1:15 API: polymer ratios for PVP and 1:5 for Soluplus^®, which ensures the solubility of GML-3 in purified water and maintaining the supercritical state in solution.

100 项与 GHF-201 相关的药物交易

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