Benzenesulfonamide upregulators of NPC1 for Neimann-Pick disease and other lysosomal storage disorders
Inventors
Patnaik, Samarjit • TAYLOR, Mercedes • Calvo, Raul Rolando • Marugan, Juan Jose • Southall, Noel • Zheng, Wei • Ferrer-Alegre, Marc • DEHDASTHI, Seameen • Dranchak, Patricia • CHEN, Fannie • Ioannou, Yiannis
Assignees
Icahn School of Medicine at Mount Sinai • US Department of Health and Human Services
Publication Number
US-10239830-B2
Publication Date
2019-03-26
Expiration Date
2036-02-11
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Methods and compositions for treating lysosomal storage disorders are disclosed. The methods involve administering a genus of benzenesulfonamides, particularly N-[3-(aminosulfonyl)phenyl]-benzamides and heteroarylamides. A genus of suitable compounds is shown in formula 1:
Core Innovation
The invention relates to methods and compositions for treating lysosomal storage disorders (LSDs) by administering a genus of benzenesulfonamides, specifically N-[3-(aminosulfonyl)phenyl]-benzamides and heteroarylamides. These compounds of formula I are aimed at upregulating the NPC1 promoter to enhance endogenous levels of NPC1 protein, which plays a critical role in cholesterol and lipid transport within cells.
Lysosomal storage disorders are a group of inherited metabolic diseases caused by deficiencies in lysosomal proteins leading to accumulation of various substrates inside lysosomes, resulting in cellular and organ dysfunction. Notably, Niemann-Pick type C (NPC) disease is caused by mutations in the NPC1 gene and leads to accumulation of cholesterol and lipids in the late endosomal/lysosomal system, causing fatal progressive neurological disease with no current effective treatment options targeting the central nervous system.
The invention addresses the problem of treating NPC and other LSDs by proposing small molecule compounds that upregulate mutant NPC1 and/or Rab9 protein levels, thereby increasing the amount of properly folded NPC1 protein that escapes degradation and restores lipid transport. This upregulation reduces lipid accumulation and ameliorates the disease phenotype, offering a pharmacological approach suitable for crossing the blood-brain barrier and treating CNS components of lysosomal storage diseases.
Claims Coverage
The patent includes two independent claims, covering methods of treating lysosomal storage disorders using specific benzenesulfonamide compounds and the compounds themselves with particular structural features.
Method of treating lysosomal storage disorders with benzenesulfonamide compounds
A method comprising administering a compound of formula I having defined substituents R1, R2, R3, R4, R5, R6, and Cy, where these substituents encompass hydrogen, alkyl groups, various substituted phenyl or heterocyclic rings, and wherein the compounds upregulate NPC1 promoter activity to treat lysosomal storage disorders.
Benzenesulfonamide compound structures with specific substituents
Compounds of formula I and related formulas characterized by variations in R1, R2, R3 groups and the Cy ring, including optionally substituted heterocycles such as imidazole, pyridine, and phenyl, with substituent patterns that include halogen, alkyl, acyl, haloalkyl, and alkoxy groups, designed to effect NPC1 upregulation.
The claims cover methods for treating lysosomal storage disorders by administering structurally defined benzenesulfonamide compounds that upregulate the NPC1 promoter, and the compounds themselves with specific substituent profiles optimized for therapeutic efficacy.
Stated Advantages
Compounds of formula I demonstrate excellent activity in clearing cholesterol and glycosphingolipids from NPC1 patient fibroblast cell lines.
Upregulation of endogenous mutant NPC1 increases the properly folded NPC1 protein fraction, reducing its degradation and restoring lipid transport.
Compounds have the ability to cross the blood-brain barrier, enabling treatment of CNS manifestations of lysosomal storage diseases such as Niemann-Pick, Batten, and Gaucher Type II.
The invention provides a pharmacological approach that can treat lysosomal storage disorders with neuropathology, where enzyme replacement therapies are limited due to CNS accessibility issues.
Documented Applications
Treatment of lysosomal storage disorders including Niemann-Pick type C, Fabry disease, Farber disease, Gaucher's disease, Sanfilippo's syndrome, Wolman disease, Krabbe disease, MPS VII, Neuronal Ceroid Lipofuscinosis Type 2 (CLN 2), and Pompe disease.
Use of compounds to reduce cholesterol and glycosphingolipid accumulation in patient cells and animal models of lysosomal storage diseases.
Pharmaceutical formulations for oral, parenteral, rectal and topical administration to patients with lysosomal storage disorders.
Assessment and application of compounds to improve lipid transport defects and lower lipid storage in cellular and animal lysosomal storage disorder models.
Interested in licensing this patent?