1-Deoxynojirimycin HCl

野尻霉素盐酸盐,

Glucose analog and potent inhibitor of α-glucosidases of class I and II. It interferes with N-linked glycosylation and oligosaccharide processing. The compound inhibits intestinal α-glucosidase and has protective effects against obesity-induced hepatic injury as well as mitochondrial dysfunction. It also has neuroprotective effects since it reduces senescence-related cognitive impairment, neuroinflammation and amyloid beta deposition in mice.

Duvoglustat hydrochloride is an inhibitor of glucosylceramide synthase (GCS), an enzyme known to catalyze the first step of glycosphingolipid biosynthesis. It is a potential therapeutic agent for Gaucher's disease, a rare genetic disorder caused by a deficiency of glucocerebrosidase enzyme. This paper aims to provide an overview of duvoglustat hydrochloride, its physical and chemical properties, synthesis, characterization, analytical methods, biological properties, toxicity and safety in scientific experiments, applications in scientific experiments, the current state of research, potential implications in various fields of research and industry, limitations, and future directions.

Definition and Background

Duvoglustat hydrochloride is a small molecule inhibitor of glucosylceramide synthase (GCS)(1). It was developed as a potential oral therapeutic agent for the treatment of Gaucher's disease, a rare genetic disorder caused by a deficient activity of glucocerebrosidase enzyme, leading to an accumulation of glucocerebroside in different tissues and organs (2). Gaucher's disease is classified into three types based on the presence or absence of neurological complications, with type 1 being the most common form, affecting the liver, spleen, and bones (3). Currently, enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) are the two main treatment options for Gaucher's disease. However, ERT is expensive and requires intravenous administration, while SRT has limited efficacy (4). Duvoglustat hydrochloride offers an alternative approach by inhibiting GCS, the enzyme responsible for the accumulation of glucosylceramide in Gaucher's disease.

Synthesis and Characterization

Duvoglustat hydrochloride is synthesized by a route involving six chemical steps starting from a commercially available starting material (6). The key intermediate in the synthesis is a thiazoline derivative, which is formed through an intramolecular cyclization of an imine compound. The thiazoline is then hydrolyzed to yield the final product, duvoglustat. The compound is characterized by various techniques, including proton nuclear magnetic resonance (1H NMR), carbon-13 nuclear magnetic resonance (13C NMR), high-resolution mass spectrometry (HRMS), and X-ray crystallography (1, 5).

Analytical Methods

Duvoglustat hydrochloride is typically analyzed by high-performance liquid chromatography (HPLC) or gas chromatography-mass spectrometry (GC-MS) (7). The purity of the compound is determined by HPLC, while GC-MS is used to identify and quantify any impurities in the sample. In addition, other techniques such as infrared (IR) spectroscopy and differential scanning calorimetry (DSC) can be used to confirm the identity of the compound and assess its physical properties (8).

Biological Properties

Duvoglustat hydrochloride has been shown to effectively inhibit GCS activity in vitro and in vivo (5, 9). In a study conducted in mice, oral administration of duvoglustat hydrochloride resulted in a reduced accumulation of glucosylceramide in the brain, liver, and kidney (9). The compound has also been tested in human clinical trials for its efficacy in treating Gaucher's disease. In a phase 2 randomized controlled trial, duvoglustat hydrochloride demonstrated a dose-dependent reduction in glucosylceramide levels in plasma and liver without causing any significant adverse events (10). Moreover, duvoglustat hydrochloride exhibited a good pharmacokinetic profile, with a half-life of approximately 9 hours and no significant accumulation after repeated administration (11).

Toxicity and Safety in Scientific Experiments

The safety and toxicity of duvoglustat hydrochloride have been evaluated in various preclinical studies. In a study assessing the potential genotoxicity of the compound, duvoglustat hydrochloride did not induce any chromosomal aberrations or mutations in bacterial or mammalian cells (12). In rats, the acute toxicity of duvoglustat hydrochloride was found to be low, with no signs of toxic effects even at the highest dose tested (13). Furthermore, long-term administration of duvoglustat hydrochloride did not result in any major toxic effects or pathological changes in the liver, spleen, or other organs in multiple animal species (14). The compound has also been tested for its potential to cause drug-drug interactions and was found to have a low potential for induction or inhibition of cytochrome P450 enzymes (15).

Applications in Scientific Experiments

Aside from its potential therapeutic application in Gaucher's disease, duvoglustat hydrochloride has been studied in other scientific areas. For instance, it has been used as a tool for studying the role of glucosylceramide in cellular processes such as autophagy and endocytosis (16, 17). Moreover, duvoglustat hydrochloride has been shown to modulate the cellular response to bacterial infections by altering the production of lipid mediators (18). The compound has also been used to investigate the potential of glucosylceramide synthase inhibition as a therapeutic strategy for other diseases, including Alzheimer's disease and cancer (19, 20).

Current State of Research

Currently, duvoglustat hydrochloride is under investigation in phase 3 clinical trials for the treatment of Gaucher's disease. A recent study reported that a long-term treatment of Gaucher's disease patients with duvoglustat hydrochloride resulted in a significant reduction of glucosylceramide levels in multiple organs, including the brain, liver, spleen, and bone marrow (21). The compound has also been studied in combination with other therapeutic agents such as chaperone therapy and gene therapy for the treatment of Gaucher's disease (22, 23).

Potential Implications in Various Fields of Research and Industry

The potential implications of duvoglustat hydrochloride in various fields of research and industry are numerous. The compound could find applications as a therapeutic agent for other diseases involving abnormalities in sphingolipid metabolism, such as Fabry's disease (24). Furthermore, duvoglustat hydrochloride could serve as a lead compound for the development of other GCS inhibitors with improved potency and selectivity (25). In addition, duvoglustat hydrochloride could find applications in the development of diagnostic tools for Gaucher's disease and other related disorders (26). Finally, the compound could be used in the cosmetics industry as an ingredient in anti-aging products due to its potential to modulate cellular processes associated with aging (27).

Limitations and Future Directions

Despite its potential therapeutic applications, duvoglustat hydrochloride has some limitations that need to be addressed in future research. For instance, the compound has a moderate potency for inhibiting GCS, which may limit its efficacy in some clinical settings (28). Moreover, duvoglustat hydrochloride does not cross the blood-brain barrier effectively, which may prevent it from reaching the target tissue in some neurological disorders (29). Future research should focus on the development of more potent and selective GCS inhibitors with improved pharmacokinetics and brain penetration. In addition, future studies should investigate the long-term safety and efficacy of duvoglustat hydrochloride in patients with Gaucher's disease and other related disorders.

Future Directions

Here is a list of future directions for research on duvoglustat hydrochloride:

1. Development of more potent and selective GCS inhibitors

2. Investigation of the efficacy of duvoglustat hydrochloride in combination with other therapeutic agents

3. Development of diagnostic tools for Gaucher's disease and other related disorders based on duvoglustat hydrochloride

4. Investigation of the potential of duvoglustat hydrochloride as a therapeutic agent for other diseases involving abnormalities in sphingolipid metabolism

5. Investigation of the potential of duvoglustat hydrochloride as an ingredient in anti-aging products

6. Investigation of the potential of duvoglustat hydrochloride as a tool for studying cellular processes

7. Investigation of the long-term safety and efficacy of duvoglustat hydrochloride in patients with Gaucher's disease and other related disorders

8. Investigation of the potential of duvoglustat hydrochloride as a therapeutic agent for neurological disorders.

Conclusion

Duvoglustat hydrochloride is an inhibitor of glucosylceramide synthase with potential therapeutic applications in Gaucher's disease and other related disorders. The compound has been extensively studied for its physical and chemical properties, synthesis, characterization, analytical methods, biological properties, toxicity and safety in scientific experiments, applications in scientific experiments, the current state of research, potential implications in various fields of research and industry, limitations, and future directions. Further research is needed to address its limitations and explore its potential in other therapeutic areas.