Polypharmacophoric agents

Abstract

One aspect of the present invention relates to polypharmacophoric compounds. In certain embodiments, the polyphamacophore compounds comprise individual pharmacophore units selected from the group consisting of D-1 agonists, D-2 agonists, D-3 agonists, D-4 agonists, irreversible monoamine inhibitors, reversible monoamine inhibitors, monoamine transporter inhibitors, COMT inhibitors, MAO inhibitors, and dopamine transporter inhibitors. Moreover, the present invention also relates to combinatorial libraries of polypharmacophoric compounds. Another aspect of the present invention relates to the use of a polypharmacophoric compound in a method of treating a mammal in need thereof. For example, a polypharmacophoric compound of the present invention may be used in a method of treating a mammal afflicted with Alzheimer's Disease, Huntington's Disease, depression, attention deficit disorder, autism, obesity, or inflammation.

Description

RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 60 / 175,617, filed Jan. 11, 2000.BACKGROUND OF THE INVENTION [0002] The degeneration of 50-70% of the population of dopaminergic neurons in the human brain results in the profound disturbances of motor function that are characteristic of Parkinson's Disease (PD). As this degeneration of neurons progresses, the symptoms become increasingly severe, leading not only to loss of motor function but also to an increased incidence of dementia and other neurological disorders. Currently, over a million people in North America are affected by this disease whose single most consistent risk factor is age. Because the population of the elderly is expected to increase over the next four decades, it is projected that neurodegenerative diseases, such as Parkinson's Disease, may pass cancer as the second most common cause of death among the elderly. Therefore, the development of...

AI Technical Summary

Benefits of technology

"The present invention provides polypharmacophoric scaffolds and libraries thereof that can interact with multiple biological sites and elicit biological responses. These scaffolds have a scaffold unit with at least two pharmacophore units appended thereto, which can elicit a response at two or more biological receptor sites that act in concert. The pharmacophores can be selected to interact at a biological site in the region of the dopaminergic neuron, which is involved in various neurological disorders. The scaffolded polypharmacophores can be used to treat diseases or conditions that implicate the dopaminergic neuron. The invention also provides methods for making these scaffolds and libraries."

Problems solved by technology

As this degeneration of neurons progresses, the symptoms become increasingly severe, leading not only to loss of motor function but also to an increased incidence of dementia and other neurological disorders.

Protective therapy with selective monoamine oxidase B (MAO-B) inhibitors, such as selegiline, has been unproductive to date.

This remains an important area for medical research, due to the problems that exist with current therapeutic interventions.

There is clearly a beneficial motor response to this drug during the early states of the disease, however, as the disease progresses, the effectiveness of the drug is reduced and other side effects become more pronounced.

Even the DA agonists, when used as monotherapeutic agents, often fail to exceed the effectiveness of levodopa.

As such, they are subject to limitations often associated with combination therapy, for example, noncompliance due to different dosing schedules and drug-drug interactions.

Because of this decreased response, often a greater dose must be utilized which often results in adverse side effects.

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