Multimediator transporter inhibitors for use in treatment of central nervous system disorders

A technology of inhibitors and transporters, applied in nervous system diseases, data processing applications, metabolic diseases, etc., can solve problems such as side effects, intolerance, inability to prevent or cure

Inactive Publication Date: 2009-11-04
PREXA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Although pharmacopoeias now offer a variety of medications for depression and related anxiety disorders and movement disorders, none of these medications can prevent or cure these conditions
Moreover, the most effective treatments are often accompanied by intolerable side effects

Method used

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  • Multimediator transporter inhibitors for use in treatment of central nervous system disorders
  • Multimediator transporter inhibitors for use in treatment of central nervous system disorders
  • Multimediator transporter inhibitors for use in treatment of central nervous system disorders

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0159] Dosage form matrices can be prepared by methods known in the polymer art. In one method of preparation, 3-5 or more casting compositions are prepared independently, wherein each casting composition contains increasing doses of drug covering each composition from low to high doses. This produces a series of layers that together form a unit polymer matrix with a concentration gradient. In another method of preparation, higher doses are prepared first, followed by layering with layers of decreasing doses, resulting in a polymer matrix with a drug concentration gradient. An example of preparing a dosage form includes mixing a pharmaceutically acceptable carrier such as polyethylene glycol with a known dose of inhibitor, incorporating it into a silicone rubber medical grade elastomer with a crosslinking agent such as stannous octoate, followed by casting in a mold. Repeat this step for subsequent layers.

[0160] The system is allowed to run, for example, for 1 hour, resul...

Embodiment 1

[0314] Example 1: Antagonism and functional activity of dopamine receptors or transporters

[0315] The functional activity of compounds is determined in vitro in cellular assays using recombinant human cell lines. According to the method of Gu et al. (J.Biol.Chem.269:27124, 1994), the functional activity of serotonin uptake inhibition was determined in human HEK-293 cell line, with fluoxetine (EC 50 =57nM) was used as a reference compound. According to the method of Galli et al. (J.Exp.Biol.198:2197,1995), the functional activity of norepinephrine uptake inhibition was determined with MDCK cell line, and desipramine (EC 50 =7nM) was used as a reference compound. To determine dopamine functional activity, the hDAT cell line was used as described by Giros et al. (Mol. Pharmacol. 42:383, 1992), with nomifensine (EC 50 =11 nM) was the reference compound.

[0316] Table 1, human (h) and rat (r) in vitro functional absorption distribution profiles

[0317] compound

...

Embodiment 2

[0335] Example 2: In vivo potency of several exemplary dopamine transporter inhibitors

[0336] The in vivo potency of several exemplary inhibitors (1), (3) and (4) of the invention was determined using a standard forced swim test model in rats. The aim of this study was to evaluate the antidepressant effect of test compounds in a behavioral despair assay in rats using a modified method described in: Porsolt R.D.etal.in Behavioral despair in rats: a new model sensitive to antidepressanttreatment, Eur.J Pharmacol., 47:379-391, 1978; Porsolt et al., Nature 266:730-732, 1977; and Porsolt et al., in Psychopharmacology, Olivier, Mos, and Slangen (eds) Birkhauser Verlag, Basel, pp. .137-159, 1991. In simple terms, when mice (or rats) are forced to swim within a cylinder from which escape is impossible, they readily adopt a characteristic immobility posture and no longer attempt to escape, except for requiring small movements to remain afloat. Immobility has been suggested to refle...

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PUM

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Abstract

The invention provides a class of inhibitors, packaged pharmaceuticals comprising such inhibitors, and uses of the inhibitors in treating, or the manufacturing medicaments for treating central nervous system disorders, including depression, anxiety, sleep disorders, obesity, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), sexual dysfunction, substance abuse, and movement disorders. Related business methods, such as methods for conducting a pharmaceutical business and methods for conducting a medical assistance reimbursement program, are also provided.

Description

[0001] related application [0002] This application claims priority to US Provisional Patent Application No. 60 / 839,403, filed August 21, 2006, which is hereby incorporated by reference in its entirety. Background of the invention [0003] Neuronal signals are transmitted between cells at specific points of contact called synapses. These signals are typically transmitted across synapses by the diffusion of soluble neurotransmitter molecules from presynaptic to postsynaptic cells. The release of neurotransmitters is triggered by changing the electrical potential in the presynaptic cell. These neurotransmitters rapidly diffuse across the synaptic cleft and trigger electrical changes in the postsynaptic cell by binding to neurotransmitter-gated ion channels. Excess neurotransmitters are rapidly removed from the synaptic cleft, either by specific enzymes or by reuptake into presynaptic cells or surrounding glial cells. Reuptake is mediated through a variety of neurotransmitte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22A61P25/00A61K31/445
CPCC07D211/22G06Q99/00A61P3/04A61P25/00A61P25/08A61P25/14A61P25/16A61P25/20A61P25/22A61P25/24A61P25/28A61P25/36A61P43/00
Inventor J·R·豪斯克
Owner PREXA PHARMA
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