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Pharmaceutical formulations comprising neurotrophin mimetics

a technology of neurotrophin and formulation, applied in the field of neurodegenerative and other disorders, can solve the problems of increasing the chance of adverse effects and ligands not engaging, and achieve the effect of improving the chances of adverse effects

Inactive Publication Date: 2015-04-23
U S GOVERNMENT REPRESENTED BY THE DEPT OF VETERANS AFFAIRS +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes methods for treating neurodegenerative or other disorders by administering a compound that specifically targets a p75NTR receptor molecule. The compounds can be mimetics of neurotrophin n-turn loop or other small molecules or peptides. The methods can involve treating neural, oligodendrocyte, or other cell survival by administering the compound. The compounds can be used to treat various conditions involving degeneration or dysfunction of cells expressing p75NTR. The patent also describes specific compounds that can be used for the treatment of Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, pick's disease, peripheral neuropathy, and other disorders.

Problems solved by technology

Additionally, the highly pleiotropic effects of neurotrophins achieved through action of the dual receptor signaling network increases the chances of adverse effects.
However, these monomeric ligands may not engage the receptor in the same way as the natural ligands.

Method used

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  • Pharmaceutical formulations comprising neurotrophin mimetics
  • Pharmaceutical formulations comprising neurotrophin mimetics
  • Pharmaceutical formulations comprising neurotrophin mimetics

Examples

Experimental program
Comparison scheme
Effect test

example 1

Computational Modeling, Pharmacophore Generation, Virtual and Functional Screening

[0229]In order to generate a productive pharmacophore emulating a loop structure likely to interact with a receptor, it was hypothesized that (1) the degrees of freedom of the ligand peptide structure are restricted by its residence in the protein, and (2) there is little “induced fit” involving changes in loop structure at the targeted receptor subsite, or it is accommodated by flexibility of the small molecule ligand. When both of these conditions apply, they allow an interacting / activating small molecule conformation that interacts with the receptor in a manner similar to that of the native ligand.

[0230]Computational studies of active dimeric cyclic peptides mimicking NGF β-hairpin loops suggest that energetic and structural constraints would disallow simultaneous β-hairpin folding of both peptide subunits, implying that the peptides act in a monomeric fashion. Additionally, based on early virtual s...

example 2

Compounds Promote Hippocampal Neuron Survival

[0235]High-throughput virtual screening based on neurotrophin loop 1 models and small-scale in vitro bioassays were used to identify chemically diverse compounds with potent neurotrophic activity (FIG. 1). Approximately 800,000 compounds were screened in silico to produce a high yield of 4 positives out of 23 compounds submitted to in vitro screening (17%).

[0236]In order to understand the mechanisms of action of the selected compounds and test the conjecture that they work via the targeted receptor, p75NTR the dose-dependent relationships of the survival-promoting activities of the p75-binding compounds compared to NGF and BDNF using embryonic hippocampal neurons in culture conditions in which NGF promotes neural survival were examined. In the cultures, neurotrophic activity was mediated by BDNF principally through TrkB and p75NTR and by NGF primarily through p75NTR, as they express little TrkA (Brann, A. B., et al. (1999) J Neurosci 19, ...

example 3

Compounds Interact With and Work Through p75NTR Receptors, Not Trk Receptors

[0241]In order to assess the interactions of the p75-binding compounds with neurotrophin receptors, the effects of increasing concentrations of compounds on NGF binding to the recombinant chimeric proteins p75NTRNTR-Fc and TrkA-Fc were examined. In these experiments, Compound 4 (FIG. 3a) and Compound 3 (FIG. 3b), but not Compound 5 (FIG. 3c), shifted the NGF / p75NTR-FC biding curve significantly to the right. The inhibition of NGF binding caused by each active compound was reversed with increasing NGF concentration, consistent with a mechanism that is, at least in part, competitive in nature. When the data was fit to the Gaddum-Schild equation that describes ligand binding in the presence of an inhibitor (Motulsky, H.J., and Christopoulos, A. (2003) A Practical Guide to Curve Fitting, 2nd edn. (San Diego, Calif., GraphPad Software, Inc.)), the resulting Schild coefficients were significantly less than 1.0 for...

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Abstract

Methods and compounds for treating neurodegenerative and other disorders. Included is the administering to a subject in need thereof an effective amount of a compound having binding specificity for a p75NTR receptor molecule. Enhanced survival of neural and other cells has been observed.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. patent application Ser. No. 12 / 762,947, filed on Apr. 19, 2010, herein incorporated by reference in its entirety, which is a continuation of U.S. patent application Ser. No. 11 / 396,936, filed on Apr. 3, 2006, herein incorporated by reference in its entirety, which is based on and claims priority to U.S. Provisional Application Ser. No. 60 / 671,785, filed Apr. 15, 2005, herein incorporated by reference in its entirety.GRANT STATEMENT[0002]This invention was made with government support under Grant NS030687 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD[0003]The presently disclosed subject matter generally relates to the treatment of neurodegenerative and other disorders in a subject. More particularly, the methods of the presently disclosed subject matter relate to administering to a subject an effective amount of a compound having bin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/522
CPCA61K31/522A61K31/155A61K31/445A61K31/496A61K31/497A61K31/537C07K2317/76C07K16/2878A61K31/519A61P17/14A61P21/02A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P43/00A61P9/00A61P9/10A61P3/10
Inventor LONGO, FRANK M.MASSA, STEPHEN M.
Owner U S GOVERNMENT REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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