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1h-pyrazol-1-yl-thiazoles as inhibitors of lactate dehydrogenase and methods of use thereof

A C1-C5, C1-C4 technology, applied in the direction of medical preparations containing active ingredients, pharmaceutical formulas, drug combinations, etc., can solve problems such as poor bioavailability

Active Publication Date: 2019-07-09
US DEPT OF HEALTH & HUMAN SERVICES +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-thiazoles as inhibitors of lactate dehydrogenase and methods of use thereof
  • 1h-pyrazol-1-yl-thiazoles as inhibitors of lactate dehydrogenase and methods of use thereof
  • 1h-pyrazol-1-yl-thiazoles as inhibitors of lactate dehydrogenase and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0114] Test compounds were placed in Greiner Bio-One (Monroe, NC) 1536-well black solid bottom assay plates. As assay buffer, use 200 millimolar (mM) Tris HCl, pH 7.4, 100 micromolar (μM) EDTA and 0.01% TWEEN-20 TM , the final concentration. The LDHA reagent was 2 nanomolar (nM) human LDHA (Meridian LifeScience, Inc., Memphis, TN), final concentration, in assay buffer. In assay buffer, substrate reagents were 0.06 mM NADH and 0.2 mM sodium pyruvate, final concentrations. The resazurin / diaphorase coupling reagent was 0.037 mM resazurin and 0.133 milligrams per milliliter (mg / mL) diaphorase in assay buffer, final concentration. The sequence of steps, the amount 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 emission.

[0115] Tab...

Embodiment 2

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

[0119] Test compounds were placed in Greiner Bio-One (Monroe, NC) 1536-well black solid bottom assay plates. As assay buffer, use 200 mM Tris HCl, pH 7.4, 100 μM EDTA and 0.01% TWEEN-20 TM , the final concentration. LDHB reagent was 2 nM human LDHB (Meridian Life Science, Inc., Memphis, TN) at final concentration in assay buffer. In assay buffer, substrate reagents were 0.13 mM NADH and 0.16 mM sodium pyruvate, final concentrations. The resazurin / diaphorase coupling reagent was 0.037 mM resazurin and 0.133 mg / mL diaphorase in assay buffer, final concentration. The sequence of steps, the amount 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 the human PHGDH pair screening biochemical assay used to characterize compounds of formula (I) in one embodiment of the invention.

[0124] Test compounds were placed in Greiner Bio-One (Monroe, NC) 1536-well black solid bottom assay plates. As assay buffer, use 50 mM TEA, pH 8.0, 10 mM MgCl 2 , 0.05% BSA, and 0.01% TWEEN-20 TM , the final concentration. In assay buffer, 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. PHGDH reagent is 0.15 mM NAD in assay buffer + and 10 nM human PHGDH, final concentrations. The sequence of steps, the amount 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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PUM

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Abstract

The invention provides a compound of the formula (II) and pharmaceutically acceptable salts thereof. The variables, e.g. n, R, R3, R10, X, Y, and Z are defined herein. These compounds act as lactate dehydrogenase inhibitors and are useful for treating cancer and fibrosis. The compounds may be particularly useful for treating forms of cancer in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred. The invention also provides pharmaceutical compositions containing a compound of this formula and a method for treating patients having cancer, fibrosis, or other conditions in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred.

Description

[0001] Citations to related applications [0002] This application claims priority to US Provisional Application No. 62 / 356,065, filed June 29, 2016, which is hereby incorporated by reference in its entirety. Background technique [0003] Agents that target enzymes involved in cancer cell metabolism offer attractive therapeutic avenues since it is possible to preferentially target cancerous tissue over normal tissue. While normal tissues typically use glycolysis only when oxygen supply is insufficient, cancer tissue relies heavily on aerobic glycolysis independent of oxygen supply levels. This property is called the Warburg effect (Vander Heide et 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 decreased rate of pyruvate entry into the TCA (tricarboxylic acid) cycle and the concomitant increase in lactate production are critical for tumor growth and survival. LD...

Claims

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Application Information

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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 US DEPT OF HEALTH & HUMAN SERVICES
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