Use of thyroid beta-agonists

Inventors

Lian, Brian • Hanley, Rochelle • Dinerman, Misha • Erion, Mark • Boyer, Serge • Jiang, Hongjian

Assignees

Metabasis Therapeutics Inc • Viking Therapeutics Inc

Abstract

Methods useful for treating X-linked adrenoleukodystrophy are provided.

Core Innovation

The disclosure addresses X-linked adrenoleukodystrophy, including cerebral ALD and adrenomyeloneuropathy, and describes treating a subject with a thyroid hormone receptor beta agonist that is a phosphonic acid containing compound of Formula I or a salt or ester thereof. The compounds are defined using Formula I with variable definitions for G, T, R1-R5, Y/Y′, and X as the phosphonate motif, and the disclosure includes preferred exemplary compounds provided in Table I.

The document discloses prodrug concepts for phosphonate and phosphonic acid derivatives, including structural classes in which a phosphonate/phosphonic acid parent compound is enzymatically hydrolyzed after prodrug conversion. It describes para-substituted benzyl/phosphonate esters, thio-containing phosphonate proesters, fused lactones, optionally substituted alicyclic carbonate and thiocarbonate examples, propyl phosphonate proesters with cyclic hydroxyl derivatives, cyclic phosphoramidates, and combination prodrug types such as S-acyl-2-thioethyl ester and phosphoramidate prodrug types.

The disclosure further describes methods of administering the thyroid hormone receptor beta agonist or selected prodrug compound to treat X-linked adrenoleukodystrophy, including administration schedules such as daily, every other day, and intermittent cycles such as 3 months on followed by 1 month off. It also describes pharmaceutical dosage forms and administration routes including tablet, capsule, solution, injection, transdermal patch, and eye drop, with formulations including effective amounts of the compounds together with pharmaceutically acceptable excipients.

Claims Coverage

The partial content grounds coverage in independent claim families directed to treating X-linked adrenoleukodystrophy by administering a phosphonic acid containing thyroid hormone receptor beta agonist compound of Formula I or a selected prodrug compound, including salts or esters thereof. The claim sets also include refinements tied to depicted structures, phenolic hydroxyl and phosphonate features, and an intermittent dosing regimen, with six cited claim members referenced across the items.

Across the explicitly referenced claim members, coverage centers on administering a depicted thyroid hormone receptor beta agonist phosphonic acid-containing compound or selected prodrug compound, including salts or esters, for treating X-linked adrenoleukodystrophy, with refinements requiring correspondence to a depicted structure, inclusion of phenolic hydroxyl and phosphonate features, and an intermittent dosing schedule including a 3-month on/1-month off regimen.

Stated Advantages

Documented Applications