1-Deoxygalactonojirimycin HCl

1-脫氧半乳糖野尻霉素鹽酸鹽,

Specific and potent inhibitor of lysosomal α-galactosidase with IC50 in nanomolar range. It acts as pharmacological chaperone and assists folding of the wild type and mutant versions of the enzyme. It places itself in the instable active site and prevents the damage to the enzyme during the passage through Golgi apparatus, endoplasmatic reticulum and lysosome axis. The exposure to this compound leads to increased levels of functional α-galactosidase in models for lysosomal storage disorders and brings therapeutic benefits to patients with Fabry disease.

Definition and background: 

Migalastat hydrochloride is a pharmacological agent under clinical investigation for the treatment of Fabry disease, a rare X-linked inherited disorder. This disease is characterized by deficient activity of the lysosomal enzyme alpha-galactosidase A, leading to the accumulation of glycosphingolipids in various tissues. Migalastat hydrochloride specifically targets the mutant forms of the enzyme, restoring its activity and reducing the deposition of the glycolipids.

Synthesis and Characterization: 

Migalastat hydrochloride is synthesized through a multi-step process starting from commercially available starting materials. The steps involve N-alkylation, thiophene formation, urea formation, dehydration, and quinoline coupling. The final product is purified by column chromatography and characterized by NMR, IR, and MS spectroscopy.

Analytical Methods: 

The identification and quantification of migalastat hydrochloride in biological samples and formulations can be achieved by several analytical methods. These include high-performance liquid chromatography (HPLC) with UV or mass spectrometry detection, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and capillary electrophoresis (CE). These methods can provide accurate and precise measurements of migalastat hydrochloride concentrations and its metabolites in different matrices.

Biological Properties: 

The pharmacodynamics and pharmacokinetics of migalastat hydrochloride have been extensively studied in vitro and in vivo. The compound has shown high affinity and selectivity for the target mutant forms of alpha-galactosidase A, leading to enzyme stabilization and increased activity. The oral bioavailability of migalastat hydrochloride is moderate, with a Tmax of 2-4 hours and a half-life of 4-8 hours. The compound undergoes moderate hepatic metabolism and is excreted mainly in the feces.

Toxicity and Safety in Scientific Experiments: 

Animal studies and clinical trials have demonstrated the safety of migalastat hydrochloride in terms of toxicity and adverse effects. The compound has shown no genotoxicity or carcinogenicity in vitro or in vivo. Some side effects have been reported in clinical trials, such as headache, dizziness, nausea, and diarrhea. However, these were generally mild to moderate and reversible.

Applications in Scientific Experiments: 

Migalastat hydrochloride has been used in various scientific experiments and preclinical studies related to Fabry disease and glycolipid metabolism. These applications include the evaluation of its efficacy in reducing glycolipid levels in animal models, its interaction with different alpha-galactosidase A mutations, and its combination with other pharmacological agents. Migalastat hydrochloride has also been investigated in clinical trials for its safety and efficacy in patients with Fabry disease.

Current State of Research: 

Migalastat hydrochloride is currently under clinical investigation for the treatment of Fabry disease, with several ongoing clinical trials in different countries. The compound has received regulatory approval in the European Union and some other countries. The research on migalastat hydrochloride is focused on its potential clinical benefits, including its ability to improve clinical symptoms, to prevent organ damage, and to reduce the need for enzyme replacement therapy.

Potential Implications in Various Fields of Research and Industry: 

The potential implications of migalastat hydrochloride extend beyond the field of Fabry disease. The compound can be used as a tool for investigating the role of glycolipids in different biological processes, including lysosomal storage disorders, neurodegeneration, and cancer. Moreover, migalastat hydrochloride can provide insights into the mechanisms of action of pharmacological chaperones and enzyme replacement therapy, which are widely used in other diseases.

Limitations and Future Directions: 

Despite its promising potential, migalastat hydrochloride has some limitations and challenges that need to be addressed. These include the variability in its efficacy depending on the mutation type, the need for personalized medicine approaches, and the potential for easy development of resistance. Future directions of research on migalastat hydrochloride include the identification of novel mutations and their response to the compound, the evaluation of its long-term safety and efficacy, and the development of more effective formulations and delivery strategies.

In summary, migalastat hydrochloride is a pharmacological agent with promising potential for the treatment of Fabry disease and for investigating glycolipid metabolism and related diseases. The compound's physical and chemical properties, synthesis, characterization, analytical methods, biological properties, toxicity, applications, current state of research, potential implications, and future directions have been presented in this paper. The research on migalastat hydrochloride is continuously evolving, and it is hoped that it will pave the way for new therapeutic strategies and insights into the biology of glycolipids.