1h-pyrazol-1-yl-thiazole as an inhibitor of lactate dehydrogenase and methods of using the same

A thiazole, C1-C4 technology, applied in the directions of medical preparations, pharmaceutical formulations, and drug combinations containing active ingredients, can solve problems such as poor bioavailability

Active Publication Date: 2022-07-22
UNITED STATES OF AMERICA +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the in vivo bioavailability of the inhibitor was found to be poor

Method used

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  • 1h-pyrazol-1-yl-thiazole as an inhibitor of lactate dehydrogenase and methods of using the same
  • 1h-pyrazol-1-yl-thiazole as an inhibitor of lactate dehydrogenase and methods of using the same
  • 1h-pyrazol-1-yl-thiazole as an inhibitor of lactate dehydrogenase and methods of using the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] This example describes a human LDHA primary biochemical assay used to characterize compounds of formula (I) in one embodiment of the present invention.

[0114] Test compounds were placed in a Greiner Bio-One (Monroe, NC) 1536 well black solid bottom assay plate. As assay buffer, 200 millimolar (mM) Tris HCl, pH 7.4, 100 micromolar (μM) EDTA and 0.01% TWEEN-20 were used TM , the final concentration. In assay buffer, the LDHA reagent was 2 nanomolar (nM) human LDHA (Meridian LifeScience, Inc., Memphis, TN), final concentration. In assay buffer, the substrate reagents were 0.06 mM NADH and 0.2 mM sodium pyruvate, final concentrations. In assay buffer, the resazurin / diaphorase coupling agent was 0.037 mM resazurin and 0.133 milligrams per milliliter (mg / mL) diaphorase, final concentrations. The sequence of steps, the number and type of reagents, and the time required for each step are set forth in Table 1. Inhibition of LDHA activity was measured by fluorescence emissi...

Embodiment 2

[0118] This example describes a human LDHB counterscreen biochemical assay used to characterize compounds of formula (I) in one embodiment of the invention.

[0119] Test compounds were placed in a Greiner Bio-One (Monroe, NC) 1536 well black solid bottom assay plate. As assay buffer, use 200 mM Tris HCl, pH 7.4, 100 μM EDTA and 0.01% TWEEN-20 TM , the final concentration. In assay buffer, the LDHB reagent was 2 nM human LDHB (Meridian Life Science, Inc., Memphis, TN), final concentration. In assay buffer, the substrate reagents were 0.13 mM NADH and 0.16 mM sodium pyruvate, final concentrations. In assay buffer, the resazurin / diaphorase coupling agent was 0.037 mM resazurin and 0.133 mg / mL diaphorase, final concentrations. The sequence of steps, the number and type of reagents, and the time required for each step are set forth in Table 2. Inhibition of LDHB activity was measured by fluorescence emission.

[0120] Table 2

[0121]

Embodiment 3

[0123] This example describes a human PHGDH pair screening biochemical assay used to characterize compounds of formula (I) in one embodiment of the present invention.

[0124] Test compounds were placed in a Greiner Bio-One (Monroe, NC) 1536 well black solid bottom assay plate. As assay buffer, 50 mM TEA, pH 8.0, 10 mM MgCl was used 2 , 0.05% BSA, and 0.01% TWEEN-20 TM , the final concentration. In assay buffer, the substrate reagents were 10 μM EDTA, 0.625 mM glutamate, 500 nM human PSAT1, 500 nM human PSPH, 0.05 mM 3-phosphoglycerate, 0.1 mM resazurin, and 0.1 mg / mL diaphorase, final concentration. In assay buffer, PHGDH reagent is 0.15 mM NAD + and 10 nM human PHGDH, final concentration. The sequence of steps, the quantity and type of reagents, and the time required for each step are set forth in Table 3. Inhibition of PHGDH activity was measured by fluorescence emission.

[0125] table 3

[0126]

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Abstract

The present disclosure provides compounds of formula (II) and pharmaceutically acceptable salts thereof. Variables such as n, R, R 3 , R 10 , X, Y and Z are defined herein. These compounds act as inhibitors of lactate dehydrogenase and are used in the treatment of cancer and fibrosis. The compounds may be particularly useful in the treatment of forms of cancer in which metabolic transformation from oxidative phosphorylation to glycolysis occurs. The present disclosure also provides pharmaceutical compositions containing compounds of this formula and methods for treating patients with cancer, fibrosis, or other disorders in which the metabolic transition from oxidative phosphorylation to glycolysis occurs.

Description

[0001] Citations for Relevant Applications [0002] This application claims priority to US Provisional Application No. 62 / 356,065, filed June 29, 2016, which is incorporated herein by reference in its entirety. Background technique [0003] Agents targeting enzymes involved in the metabolism of cancer cells offer attractive therapeutic avenues because it is possible to preferentially target cancerous tissue over normal tissue. While normal tissues typically use glycolysis only when oxygen supply is insufficient, cancer tissues rely heavily on aerobic glycolysis regardless of the level of oxygen supply. This property is known as the Warburg effect (Vander Heidenet al., Science, 2009, 324(5930): 1029-1033). Lactate dehydrogenase (LDH) is involved in the final step of glycolysis in which pyruvate is converted to lactate. The reduced rate of pyruvate entry into the TCA (tricarboxylic acid) cycle and the concomitant increase in lactate production are critical for tumor growth and...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04C07D417/14A61K31/427A61P35/00A61P11/00
CPCC07D417/04C07D417/14A61P11/00A61P35/00A61P43/00
Inventor 戴维·J·马洛尼亚历克斯·格雷戈里·沃特森甘尼沙·拉伊·班图卡卢凯勒·瑞恩·布里马科姆普拉门·克里斯托夫希·V·丹格维克托·M·达利-乌斯马尔马修·霍尔胡新阿吉特·贾达夫索姆纳特·贾纳金光镐威廉·J·穆尔布莱恩·T·莫特伦纳德·M·内克斯安东·西梅奥诺夫加里·艾伦·苏利科夫斯基丹尼尔·詹森·乌尔班杨世明
Owner UNITED STATES OF AMERICA
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