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Compound for reducing lipotoxic damage

A technology of compounds and compositions, applied in the field of compounds for reducing lipotoxic damage

Active Publication Date: 2020-06-26
MAYO FOUND FOR MEDICAL EDUCATION & RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As there are no effective therapies, the current standard of care when it occurs is supportive care and treatment of complications

Method used

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  • Compound for reducing lipotoxic damage
  • Compound for reducing lipotoxic damage
  • Compound for reducing lipotoxic damage

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] Example 1. Preparation and Testing of Unformylated Amino Acid Analogs

[0114] A number of unformylated amino acid analogs were prepared in which the L-amino ester leucine was replaced by a congener. The synthetic steps of this method are as follows figure 2 shown. Such as image 3 As shown, the resulting compounds include

[0115] Compounds wherein the amino ester of L-leucine (#723, is orlistat) is substituted by a congener such as N-methylleucine (#724) or a more polar or shorter congener, including L -Alanine (#716), N-Acetyl-L-Cysteine ​​(#717), L-Asparagine (#718), L-Histidine (#725), L-Methionine Acid Sulfone (#726), L-Arginine (727), L-Diaminopimelic Acid (#728), L-Serine (#729), L-Ornithine (#731), or N-Acetyl base leucine (#732).

[0116] To test the potency of these compounds, drugs were dissolved in ethanol as 20 mM stock solutions and then diluted into PBS as 600 micromolar working stocks (3.3% ethanol). This is used right away or left at room tem...

Embodiment 2

[0117] Example 2. Preparation and testing of formylated amino acid analogs

[0118] A number of formylated amino acid analogs were prepared in which the L-amino ester leucine was replaced by a congener. The synthetic steps of this method are as follows figure 2 and Figure 5 shown.

[0119] These drugs (#733,734,738,739,740,742,743, as Figure 6 indicated) was initially tested as described in Example 1. An approximately 10-fold increase in stability and potency after overnight storage was noted for compounds 741, 736 and 743 compared to orlistat (Figure 7). Compounds were further tested for their efficacy in reducing lipotoxic injury to acinar cells in acinar-adipocyte co-cultures as described in the following: Navina S, Acharya C, DeLany JP, Orlichenko LS, Baty CJ, Shiva SS, Durgampudi C, Karlsson JM, Lee K, Bae KT et al.: Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity ( Lipotoxicity causes multisystem organ failure and e...

Embodiment 3

[0120] Example 3. Preparation and testing of beta chain analogs.

[0121] To further test options for improving the potency of the analogs, the β-strand of 741 was altered to make it more hydrophilic. For this, if Figure 9-14 Compounds 760, 762, 763 were prepared as described. Modification at this position did not improve lipase inhibition and in fact a decrease in potency was observed. see Figure 15 .

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Abstract

Provided herein are novel lipase inhibitors and methods for using the same to treat inflammation, multisystem organ failure, necrotic pancreatic acinar cell death, acute pancreatitis, sepsis (e.g., culture negative sepsis), burns, and acne. For example, provided herein are two novel lipase inhibitors useful in the methods described herein (I) (II) or a pharmaceutically acceptable salt thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 531,454, filed July 12, 2017, which is incorporated herein by reference in its entirety. technical field [0003] The present disclosure relates to the use of lipase inhibitors to treat severe pancreatitis and / or acne. Background technique [0004] The pancreas produces enzymes that aid in the digestion and absorption of food; one of these is lipase, which digests fat. Some individuals, such as obese individuals, are at risk of developing multisystem organ failure under acute inflammatory conditions, such as severe burns, severe trauma, critical illness and acute pancreatitis (AP) conditions. Pancreatitis is associated with the release of destructive digestive enzymes into the pancreas by pancreatic acinar cells. When AP occurs, it quickly becomes severe AP (SAP). Worryingly, SAP causes 40-50% of deaths when accompanied by acute renal fai...

Claims

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Application Information

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IPC IPC(8): A61K36/185A61K36/74
CPCA61K31/365A61P1/18A61P17/10A61P31/00A61P17/02A61P31/04A61P11/00C07D205/08A61P3/04C07D305/12
Inventor S-K·安娜但K·格林曼Z·卡马尔V·P·辛格
Owner MAYO FOUND FOR MEDICAL EDUCATION & RES
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