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Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof

a technology of mitochondrial aldehyde and modulator, which is applied in the direction of drug composition, anti-noxious agents, metabolic disorders, etc., can solve the problems of ischemia of some organs, interruption of blood flow,

Inactive Publication Date: 2009-03-26
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In some circumstances, such as during surgery, interruption of blood flow resulting in ischemia of some organ is unavoidable.

Method used

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  • Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof
  • Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof
  • Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Identification and Characterization of ALDH2 Agonists

Methods

In Vitro Screen for ALDH2 Agonists (Activators) and Antagonists (Inhibitors)

[0323]Compounds were screened using a method as depicted schematically in FIG. 2. Essentially, the reaction is carried out at 25° C. in 0.1 NaPPi buffer, pH 9.5, 2.4 mM NAD+ and 10 mM acetaldehyde as the substrate. Enzymatic activity is measured by a reductive reaction of NAD+ to NADH at 340 nm. Alternatively, the production of NADH can be coupled with another enzymatic reaction that consumes NADH and that provides for a detectable signal. An example of such an enzymatic reaction is a diaphorase-based reaction, which reduces resazurin to its oxidized fluorescent compound resorufin.

[0324]For example, a 120 μl reaction mixture for ALDH2 enzymatic activity comprises the following components:

[0325]43 μl 150 mM sodium pyrophosphate (NaPPi) buffer, pH 9.0;

[0326]30 μl 10 mM NAD+;

[0327]15 μl 80 mM acetaldehyde;

[0328]1 μl of resazurin (0.2 mg / ml in H2O);

[032...

example 2

Identification and Characterization of ALDH2 Inhibitors

[0349]Compounds were screened, as described above, but using the “wild-type” ALDH2 enzyme. Of 63,000 compounds screened, six inhibitors were identified. Three of the compounds, referred to in FIGS. 8, 9, and 10 as #062923, #046072, and #032208, respectively, were assayed for their effect on ALDH2 enzymatic activity. The results are shown in FIGS. 8-10. As shown in FIG. 8, compound #062923 inhibited ALDH2 activity at an IC50 of 0.63 μM. (Note that for FIGS. 3, 4, and 8-10, the x-axis unit is: OD at 340 nm. For FIGS. 3, 4, and 7-10, the y-axis unit is: Time (in minutes). As shown in FIG. 9, compound # 046072 inhibited ALDH2 activity at an IC50 of 1.14 μM. (FIG. 9: n=3). As shown in FIG. 10, compound # 032208 inhibited ALDH2 activity at an IC50 of 1.62 μM. (FIG. 10: n=3).

[0350]The structures of additional compounds (referred to as Compounds 8-18, above) that were identified in the initial screen as ALDH2 inhibitors are provided abo...

example 3

BDDB Protects Against Ischemia / Reperfusion Injury In Vivo

[0351]Male Wistar rats (250-300 g) were anesthetized by 3% isoflurane. The surgical procedures used for left anterior descending coronary artery (LAD) ligation are based on published protocols. Animals were intubated, and ventilated with a Harvard rodent ventilator at a rate of 80 breaths per minute (5-15 mm Hg). Maintenance anesthesia was provided via 1% inhalational isoflurane, and body temperature was maintained at 37° C. using a rectal probe linked to a thermocoupled thermometer and an appropriate heating blanket. The heart was exposed by median sternotomy. Following a 20-minute period of stabilization, a ligature was placed around the LAD coronary artery, close to its origin from the aortic root. The ends of the ligature were passed through polyethylene tubing forming a small noose in which a syringe plunger was rested upon the myocardial surface. Coronary occlusion was achieved by pressing the tubing against the plunger ...

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Abstract

The present invention provides compounds that function as modulators of mitochondrial aldehyde dehydrogenase-2 (ALDH2) activity; and pharmaceutical compositions comprising the compounds. The present invention provides therapeutic methods involving administering a subject compound, or a subject pharmaceutical composition. The present invention further provides assays for identifying agonists of ALDH2.

Description

CROSS-REFERENCE[0001]This application claims the benefit of U.S. Provisional Patent Application No. 60 / 905,963, filed Mar. 8, 2007, which application is incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH[0002]The U.S. government may have certain rights in this invention, pursuant to grant no. AA11147 awarded by the National Institutes of Health.BACKGROUND[0003]Tissues deprived of blood and oxygen undergo ischemic necrosis or infarction with possible irreversible organ damage. In some circumstances, such as during surgery, interruption of blood flow resulting in ischemia of some organ is unavoidable. In addition, in the case of solid tumors, it is desirable to interrupt the blood flow and actually induce ischemia. Once the flow of blood and oxygen is restored to the organ or tissue (reperfusion), the organ does not immediately return to the normal preischemic state. For example, in the case of the ischemic myocardium, reperfused postisch...

Claims

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Application Information

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IPC IPC(8): A61K31/34C07D317/44
CPCC07D405/12C07D317/58A61P3/10A61P9/04A61P9/10A61P9/12A61P17/18A61P19/10A61P21/02A61P25/16A61P25/28A61P25/32A61P25/36A61P35/00A61P39/02A61P39/06A61P43/00
Inventor MOCHLY-ROSEN, DARIACHEN, CHE-HONGOUYANG, XIAOHU
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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