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Publication Number
US-9132134-B2
Publication Date
2015-09-15
Expiration Date
Abstract
Provided herein are methods, compositions, and kits for the treatment of an enteric nervous system disorder. Such methods may comprise administering to a subject an effective amount of a phenothiazine compound, a peripherally restricted dopamine decarboxylase inhibitor, and/or a peripherally restricted dopamine D2 receptor antagonist that does not substantially inhibit hERG channels.
Core Innovation
The invention relates to treating gastroparesis and enteric nervous system disorders in a human subject using compounds of formula III, including pharmaceutically acceptable salt, solvate, or metabolite forms, and phenothiazine compounds including metopimazine, metopimazine acid, and prodrugs of metopimazine acid. The disclosed approach uses chronic administration for over 5 days and includes oral administration in some embodiments.
A further aspect provides combination treatment in which a dopamine decarboxylase inhibitor is co-administered with the phenothiazine compound or formula III compound. The disclosure includes peripherally restricted dopamine decarboxylase inhibitors that do not cross the blood-brain barrier, including carbidopa, S-carbidopa, and L-carbidopa.
The disclosure also describes D2 (optionally D2/D3) dopamine receptor antagonists characterized by peripherally restricted behavior, including non-blood-brain barrier crossing supported by labeled-compound detection and/or in vitro assays. It further describes minimal hERG inhibition using an assessment that includes IC50 and hERG-mediated tail current inhibition criteria, and states that example compounds enhance gastric motility/emptying in animal models without significantly increasing cardiac QTc versus dofetilide.
Claims Coverage
The independent claims cover three method types, with three inventive features: treating gastroparesis with a compound of formula III for over 5 days, treating an enteric nervous system disorder with formula III plus a dopamine decarboxylase inhibitor for over 5 days, and orally treating gastroparesis with formula III for over 5 days.
Chronic gastroparesis treatment with a compound of formula III
Chronically administering to a human subject in need thereof an effective dose or therapeutically effective amount of a compound of formula III, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, for over 5 days.
Enteric nervous system disorder treatment with formula III plus a dopamine decarboxylase inhibitor
Administering to a human subject an effective dose of a compound of formula III, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, together with an effective dose of a dopamine decarboxylase inhibitor, for over 5 days.
Oral gastroparesis treatment with a compound of formula III
Orally administering to a human subject in need thereof a therapeutically effective amount of a compound of formula III, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, for over 5 days.
Overall, the claim set is centered on chronic treatment of gastroparesis and enteric nervous system disorders using compounds of formula III, including acceptable salt, solvate, or metabolite forms, with one claim adding combination administration with a dopamine decarboxylase inhibitor.
Stated Advantages
Peripherally restricted behavior, including non-blood-brain barrier crossing.
Minimal hERG inhibition based on hERG-mediated tail current inhibition criteria.
Enhancement of gastric motility/emptying in animal models.
Not significantly increasing cardiac QTc versus dofetilide.
Peripherally restricted dopamine decarboxylase inhibitor use is described to avoid crossing the blood-brain barrier.
Minimizes hERG channel inhibition and reduces CNS penetration.
The probability that a human subject experiences an adverse cardiac side effect is not increased.
The probability of adverse extrapyramidal side effects is reduced or not increased, as stated in the disclosure context.
Documented Applications
Treating gastroparesis in a human subject by chronically administering a compound of formula III (or pharmaceutically acceptable salt, solvate, or metabolite) for over 5 days.
Treating an enteric nervous system disorder in a human subject by administering a compound of formula III together with an effective dose of a dopamine decarboxylase inhibitor for over 5 days.
Orally administering a compound of formula III for over 5 days to treat gastroparesis.
Gastroparesis treatment in a human subject.
Treatment of an enteric nervous system disorder in a human subject.
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