Sydnonimines-specific dopamine reuptake inhibitors and their use in treating dopamine related disorders
Inventors
Chen, Hao • Liu, Ming • Su, Qi • Raisinghani, Manish
Assignees
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Publication Number
US-9604945-B2
Publication Date
2017-03-28
Expiration Date
Abstract
Derivatives of Sydnonimine and its analogues, which bind selectively to dopamine transporter (DAT) proteins are useful for treating and delaying the progression of disorders and illnesses that are alleviated by inhibiting dopamine reuptake.
Core Innovation
The invention relates to sydnonimine derivatives that act as dopamine transporter (DAT)-selective dopamine reuptake inhibitors. The compounds are defined by a formula with substituent options for R1–R6 and Ra–Rc, including pharmaceutically acceptable salts, and are directed to modulating dopamine reuptake activity in a patient to address autism.
The problem addressed is the management and/or delaying of the progression of a disorder alleviated by inhibiting dopamine reuptake, where the disorder is autism. The provided content concerns DAT’s role in dopaminergic signaling and emphasizes DAT-selective agents rather than prior approaches associated with non-selective activity.
The disclosed approach emphasizes DAT protein-specific inhibitory activity and locomotor suppressant activity, with selectivity over norepinephrine transporter (NET) binding. The compounds are characterized by potency and selectivity in binding inhibition assays at 10 μM, and the invention includes formulation concepts and compound administration for treating autism.
Claims Coverage
The provided claims include four independent method claims directed to autism management, easing autism symptoms/effects, and DAT-selective inhibition based on DAT/NET selectivity. Across the independent claims, the scope is grounded by an explicitly defined sydnonimine chemical formula, including pharmaceutically acceptable salts, and in some claims by required DAT and NET binding inhibition thresholds at 10 μM or required DAT-protein-specific inhibitory and locomotor suppressant activity.
Managing and/or delaying autism progression with sydnonimine compound formula
A method of managing and/or delaying the progression of autism in a patient by administering a therapeutically effective amount of at least one compound having the formula with specified definitions of R1–R6 and Ra–Rc, or a pharmaceutically acceptable salt.
Modulating dopamine reuptake activity in autism using formula compound with DAT-specific inhibition and locomotor suppression
A method of managing and/or delaying the progression of autism by administering to a patient a therapeutically effective amount of at least one compound having the formula, or a pharmaceutically acceptable salt, wherein the compound has dopamine transporter protein-specific inhibitory activity and locomotor suppressant activity.
Easing autism symptoms/effects using selective DAT inhibitors with DAT/NET binding selectivity thresholds
A method of easing the symptoms and/or effects of autism by inhibiting DAT activity in a patient through administering a therapeutically effective amount of a selective DAT inhibitor selected from 3-(p-methylbenzyl)-sydnonimine-N-phenylcarbamoyl and 3-(phenylpropyl)-sydnonimine-N-phenylcarbamoyl, or a pharmaceutically acceptable salt, wherein the selective DAT inhibitor exhibits DAT binding inhibition ≥90% at 10 μM and NET binding inhibition ≤15% at 10 μM.
Managing and/or delaying autism progression using selected sydnonimine-N-phenylcarbamoyl derivatives
A method of managing and/or delaying the progression of autism by administering a therapeutically effective amount of at least one compound selected from 3-(p-methyl-benzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-carboxyl-benzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-fluoro-benzyl)-sydnonimine-N-phenylcarbamoyl, and 3-(phenylpropyl)-sydnonimine-N-phenylcarbamoyl, and a pharmaceutically acceptable salt.
The claim coverage centers on managing and/or delaying autism progression and easing autism symptoms/effects using administered sydnonimine derivatives or salts defined by a specific chemical formula. The main inventive scope features DAT-linked activity, DAT-protein-specific inhibitory and locomotor suppressant activity, and in one claim defined DAT/NET binding inhibition thresholds at 10 μM while restricting the selective inhibitor to specified sydnonimine derivatives.
Stated Advantages
Locomotor suppression rather than stimulation, as contrasted with sydnocarb activity described in the provided content.
DAT potency/specificity with minimal NET interaction, as expressed by required DAT and NET binding inhibition thresholds.
Lack of amphetamine conversion propensity, as stated in the provided content.
Documented Applications
Managing and/or delaying the progression of autism in a patient alleviated by inhibiting dopamine reuptake.
Easing the symptoms and/or effects of autism by inhibiting DAT activity.
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