Heterocyclic Compounds for Oral mHTT Lowering in Huntington's Disease
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Solution Overview
Problem
There are no approved disease-modifying treatments for Huntington's disease, leaving a high unmet need for medications that can slow disease progression.
Innovation Solution
Development of heterocyclic compounds represented by Formula (I) or their pharmaceutically acceptable salts, which can be administered to lower mutant huntingtin (mHTT) protein levels, thereby treating or ameliorating Huntington's disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If RNA interference therapies (viral vectors or ASO infusions) are used to lower mHTT levels, then mHTT protein levels are reduced, but the treatment requires complex surgical delivery or repeated lumbar puncture procedures
Solution Approach 1:
The patent replaces complex mechanical delivery systems (viral vectors requiring surgical injection, ASO infusions requiring lumbar puncture) with a simple oral small molecule compound that can be administered through the gastrointestinal tract, eliminating the need for invasive procedures while achieving the same mHTT reduction effect
Solution Approach 2:
The patent uses a simple, easily administered oral small molecule compound that can be taken daily without requiring complex medical procedures, replacing expensive and complex delivery systems with a practical, patient-friendly oral medication
2Reliability
If branaplam (pyridazine derivative) is used to lower mHTT levels, then mHTT protein levels are reduced in HD patient cells and mouse models, but there are no approved disease-modifying treatments for HD yet
Solution Approach 1:
The patent modifies the chemical structure of branaplam by changing the core heterocyclic scaffold from pyridazine to various heterocyclic compounds (imidazole, triazole, oxazole, thiazole, isoxazole, pyrimidine, purine, indole, carbazole, dibenzofuran, dibenzothiophene, pyridine, pyrimidine, triazine, tetrazine, pyrazole, pyridazinone, triazolinone, oxadiazole, thiadiazole, isoxazolinone, carbazolinone, dibenzofuranone, dibenzothiopheneone), creating a series of novel compounds with potentially improved therapeutic properties and pharmacological profiles
Data Source
AI summary
The present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof and its use in, e.g. treating a condition, disease, or disorder in which lowering mutant huntingtin protein (“mHTT”) in a subject is of therapeutic benefit, specifically in treating Huntington disease (“HD”). This disclosure also features a composition containing the same as well as methods of using and making the same.