Use of thyroid beta-agonists
Inventors
Lian, Brian • Hanley, Rochelle • Dinerman, Misha • Erion, Mark • Boyer, Serge • Jiang, Hongjian
Assignees
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Publication Number
US-11351183-B2
Publication Date
2022-06-07
Expiration Date
Abstract
Methods useful for treating X-linked adrenoleukodystrophy are provided.
Core Innovation
The invention is directed to a method for therapeutic treatment of X-linked adrenoleukodystrophy (X-ALD) by administering a thyroid hormone receptor beta agonist compound having a defined chemical structure, including a compound, or a salt, ester, or prodrug thereof. The description frames the problem in terms of very long chain fatty acids, peroxisomal fatty acid beta-oxidation, and ABCD1 and ABCD2 in connection with X-ALD and VLCFA.
The core compound class is described with phosphonic acid-containing and phosphonate/phosphonic acid motifs, including Formula I and related compounds identified as examples or labeled structures. The document also describes prodrug forms and related chemical motifs, including benzyl para-substituted ester prodrug motifs, thio-containing phosphonate proesters, cyclic carbonate or thiocarbonate-containing prodrug motifs, propyl phosphonate proesters, phosphoramidate derivatives, and combined S-acyl-2-thioethyl ester/phosphoramidate prodrugs.
The description states that these prodrug structures are designed to accelerate enzymatic hydrolysis or other conversion to 4-hydroxy phosphonic acids, and includes use in X-ALD models. Later sections describe reductions in VLCFA-LPC, including C26:0-LPC, in ABCD1−/− mice after compound 3, with VLCFA measurements including C20:0, C22:0, C24:0, and C26:0.
Claims Coverage
The claim coverage centers on one independent inventive feature: therapeutic treatment of X-linked adrenoleukodystrophy by administering a thyroid hormone receptor beta agonist compound having a specified structure, including salt, ester, or prodrug forms. Dependent claims further refine the claim set with dose amounts, dosing schedules, treatment interruption timing, and a narrowing to a specific labeled chemical structure.
Therapeutic treatment of X-linked adrenoleukodystrophy with a defined thyroid receptor beta agonist structure
A method of therapeutic treatment for X-linked adrenoleukodystrophy comprising administering to a subject a compound having the structure, or a salt, ester, or prodrug thereof.
Enumerated daily dose amounts for the specified-structure compound
Administering the compound at listed daily doses including 100 mg/day, 50 mg/day, 25 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, 5 mg/day, and 1 mg/day.
Every-other-day and daily dosing ranges for the specified-structure compound
Administering the compound at about 1 mg to about 100 mg every other day, or daily at about 1 mg to about 100 mg per day.
Combined administration with a thyroid hormone receptor beta agonist including interruption timing
Administering a thyroid hormone receptor beta agonist compound on a daily, every-other-day, or intermittent schedule for three months, followed by one month without administration.
Narrowing to a specific labeled chemical structure
Administering the compound as the specific chemical structure shown in the images labeled CHEM-US-00026/EMI-C00026.
The claims cover therapeutic treatment of X-linked adrenoleukodystrophy by administering a specified-structure compound, including salt, ester, and prodrug forms. Dependent claims further specify dose values, dosing schedules, a treatment interruption period, and a particular labeled chemical structure.
Stated Advantages
Reductions in VLCFA-LPC, including C26:0-LPC, are described in X-ALD model context (ABCD1−/− mice) after compound 3.
Documented Applications
Therapeutic treatment for X-linked adrenoleukodystrophy (X-ALD) by administering a specified-structure compound or a salt, ester, or prodrug form.
Use in X-ALD models including ABCD1−/− mice, with reductions in VLCFA-LPC such as C26:0-LPC and VLCFA measurements including C20:0, C22:0, C24:0, and C26:0.
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