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Identifying therapeutic compounds based on their physical-chemical properties

a technology of physical-chemical properties and therapeutic compounds, applied in the direction of antibacterial agents, material analysis, organic active ingredients, etc., can solve the problems of not always yielding active analogs, high probability of missing the most efficacious molecules, and insufficient sar alone to warrant biological activity, etc., to achieve rapid and efficient identification methods

Inactive Publication Date: 2009-06-25
AMPERE LIFE SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention is a method for identifying and selecting therapeutic compounds with a specific core structure that targets specific disorders, such as redox-based metabolic disorders, by using physical-chemical profile parameters and biological activity measurements. This method allows for the rapid and efficient identification of therapeutic compounds without the need for extensive screening with biological assays. The method is based on the premise that molecules with a specific core structure have certain physical-chemical attributes that are critical for their therapeutic effectiveness. The method can also be used to identify and select therapeutic compounds with a stilbene core structure for treating conditions characterized by oxidative stress."

Problems solved by technology

The limitation of such an approach is that it is possible to synthesize and test only a very small subset of all possible molecules thereby resulting in a high probability that the most efficacious molecules will be missed.
While widely used this method does not always yield active analogs indicating SAR alone may not be sufficient to warrant biological activity in all cases.
Although these methods are powerful they have serious limitations, such as the required amounts of target protein and the fact that the protein must be 15N-labeled to be useful for NMR studies.

Method used

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  • Identifying therapeutic compounds based on their physical-chemical properties
  • Identifying therapeutic compounds based on their physical-chemical properties
  • Identifying therapeutic compounds based on their physical-chemical properties

Examples

Experimental program
Comparison scheme
Effect test

example 1

Cyclic Voltammetry Measurement

[0147]The cyclic voltammetry measurement was conducted in a three-electrode system comprising a microelectrode made from platinum (a disk of 1.6 mm area), a counter electrode made from a coiled platinum wire and a silver / silver chloride reference electrode, on a voltammetric analyzer Epsilon with a C-3 cell, all from Bioanalytical Systems (West Lafayette, Ind.).

a. Preparation of the Solution

[0148]A solution of tetrabutyl ammonium perchlorate (TBAP) (500 mM final concentration) in N,N-dimethyl formamide (DMF) (5 mL) was prepared in a graduated flask. The compound was added to reach a concentration of 10 mM. The solution was stirred and sonicated if necessary to make sure that the compound was fully dissolved.

b. Preparation of the Electrodes

[0149]The reference electrode was kept in a 3 M solution of NaCl in distilled water. The reference electrode was rinsed with water, then methanol, and dried by air blow. The reference electrode was gently shaken, if ne...

example 2

Square Wave Voltammetry Measurement

[0157]The square wave voltammetry measurement was conducted in a three-electrode system comprising a microelectrode made from platinum (a disk of 1.6 mm2 area), a counter electrode made from coiled platinum wire and a silver / silver chloride reference electrode, on a voltammetric analyzer CV-50W with a C-3 cell, all from Bioanalytical Systems (West Lafayette, Ind.).

Procedure

[0158]a. Prepare the Solution

[0159]A solution of tetrabutyl ammonium perchlorate (TBAP) (500 mM final concentration) in N,N-dimethyl formamide (DMF) (5 mL) is prepared in a graduated flask. The compound is added to reach an arbitrary concentration, 10 mM is desired but less is acceptable. This method is especially useful for low concentration analytes, those molecules that are difficult to dissolve in DMF or available only in small quantities. The solution is stirred and sonicated if necessary to make sure that the compound is dissolved to the best of its ability.

b. Prepare the E...

example 3

Determination of Activity Utilizing the Cell Elam Assay

[0168]Endothelial-Leukocyte Adhesion Molecule (ELAM), also known as E-selectin, is expressed on the surface of endothelial cells. In this assay, lipopolysaccharide (LPS) and IL-1β were used to stimulate the expression of ELAM; test agents were tested for their abilities to reduce this expression, in accordance with studies showing that reduction of leukocyte adhesion to endothelial cell surface was associated with decreased cellular damage (e.g., Takada, M. et al., Transplantation 64: 1520-25, 1997; Steinberg, J. B. et al., J. Heart Lung Trans. 13:306-313, 1994).

[0169]Endothelial cells may be selected from any of a number of sources and cultured according to methods known in the art; including, for example, coronary artery endothelial cells, human brain microvascular endothelial cells (HBMEC; Hess, D. C. et al., Neurosci. Lett. 213(1): 37-40, 1996), or lung endothelial cells. Cells were conveniently cultured in 96-well plates. C...

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Abstract

The present invention is directed to rapid and efficient methods of identifying therapeutic compounds by allowing only the most favorable molecules initially selected based on their physical-chemical profile falling within a range predefined by the physical-chemical / biological relationship of a previously tested small subset of compounds of same core structure to be assayed; and to the therapeutic compositions identified by said methods.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. patent application Ser. No. 10 / 696,752 filed on Oct. 29, 2003, which claims priority under 35 U.S.C. 119(e) to provisional applications U.S. Ser. No. 60 / 422,727 filed on Oct. 30, 2002, and U.S. Ser. No. 60 / 487,734 filed on Jul. 16, 2003. All of those applications are incorporated herein by reference in their entirety.FIELD OF INVENTION[0002]The present invention is directed to novel methods for identifying therapeutic compounds based on their structural and physical-chemical properties, and to the therapeutic compositions identified by said methods.BACKGROUND OF THE INVENTION[0003]In response to the ever increasing demand for novel compounds useful in the effective treatment of various disorders, a variety of strategies for discovering and optimizing new therapeutics has been developed. For the most part these strategies are dependent upon techniques that allow identification of molecules binding t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/473A61K31/05A61K31/352A61P25/28A61K49/00G01N27/26G01N33/68
CPCG01N33/6893G01N2800/52G01N2500/00G01N33/6896A61P1/04A61P3/10A61P9/04A61P9/10A61P11/00A61P11/08A61P13/08A61P13/12A61P15/08A61P17/00A61P17/02A61P17/08A61P17/12A61P17/14A61P17/16A61P19/02A61P19/08A61P21/00A61P21/04A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/04A61P37/02A61P37/08A61P43/00
Inventor GILAT, SYLVAINBINYAMIN, GARYMILLER, GUY M.
Owner AMPERE LIFE SCI
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