Selective GR Modulator Compositions for Huntington's Disease
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Solution Overview
Problem
Current treatments for Huntington's Disease (HD) are mainly symptomatic and lack effective therapies targeting the underlying pathophysiology, with existing glucocorticoid receptor modulators (GRMs) like mifepristone causing side effects due to non-selectivity for the glucocorticoid receptor (GR) and other steroid hormone receptors.
Innovation Solution
Administration of selective glucocorticoid receptor modulators (GRMs), such as heteroaryl ketone fused azadecalin compounds (e.g., CORT113176 and zavacorilant), which have minimal cross-reactivity with other steroid hormone receptors, to treat HD and its symptoms, including motor, neurological, and psychological issues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective glucocorticoid receptor modulators (e.g., mifepristone) are used to treat HD, then GR activity is modulated, but side effects occur due to cross-reactivity with other steroid hormone receptors
Solution Approach 1:
The patent applies local quality by designing GRMs with specific molecular structures (heteroaryl ketone fused azadecalin or octahydro fused azadecalin) that confer selective affinity for the glucocorticoid receptor while minimizing interaction with other steroid hormone receptors. This structural differentiation enables the drug to exert its therapeutic effect specifically at the GR without causing off-target side effects from cross-reactivity.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure parameters of GRMs to achieve optimal selectivity. Specifically, the patent describes compounds with particular heteroaryl ketone fused azadecalin or octahydro fused azadecalin structures that exhibit enhanced GR binding affinity and reduced cross-reactivity compared to non-selective GRMs like mifepristone. These structural parameter modifications resolve the contradiction between efficacy and side effects.
2Ease of operation
If current symptomatic treatments are used for HD, then patient symptoms are managed, but the underlying pathophysiology is not addressed
Solution Approach 1:
The patent applies preliminary action by using GRMs to prevent and delay the onset of HD symptoms and disease progression, rather than merely managing symptoms after they occur. The selective GRMs target the underlying pathophysiology by modulating glucocorticoid receptor activity, which is implicated in HD progression, thereby addressing the root cause while also providing symptomatic relief.
Solution Approach 2:
The patent employs the glucocorticoid receptor as an intermediary target to connect symptom management with disease modification. By selectively modulating GR activity, the patent-derived GRMs simultaneously address both symptomatic relief and underlying pathophysiology, resolving the contradiction between ease of symptom management and reliable disease modification.
Data Source
AI summary
Methods and compositions for treating a patient suffering from Huntington's Disease or for treating symptoms of Huntington's Disease are disclosed. The methods include administration of an effective amount of a heteroaryl ketone fused azadecalin glucocorticoid receptor modulator (GRM) or an octahydro fused azadecalin GRM to the patient. In embodiments, the GRM is dazucorilant. In embodiments, the GRM is zavacorilant. In embodiments, the GRM is orally administered. In some embodiments, the GRM is administered daily; in other embodiments, the GRM is administered on a schedule such as, e.g., once every other day, once every three days, once per week, or other administration schedule. Symptoms of Huntington's Disease that may be treated by the present methods include, without limitation, motor symptoms (e.g., muscle weakness, postural irregularities, difficulty walking, difficulty swallowing), and neurological or psychological symptoms (e.g., epileptic seizures, amnesia; confusion; impaired speech; delirium; depression; anxiety).