Quinone reductase 2 inhibitor compounds and uses thereof

A compound and pharmaceutical technology, applied in the field of quinone reductase 2 inhibitor compound and its use, can solve problems such as limitations, efficacy and side effects, bull's eye macular degeneration, etc.

Pending Publication Date: 2021-05-28
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although CQ and HQ are often used clinically as first-line treatments for autoimmune disorders, their efficacy is limited by severe side effects
The most

Method used

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  • Quinone reductase 2 inhibitor compounds and uses thereof
  • Quinone reductase 2 inhibitor compounds and uses thereof
  • Quinone reductase 2 inhibitor compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0185] Example 1: Development of non-lysosomal aminoquinoline inhibitors of QR2.

[0186] Chloroquine and hydroxychloroquine are lysosomotropic drugs that preferentially accumulate in cellular lysosomes. For chloroquine, the pKa of the tertiary amine nitrogen is 10.32, while the pKa of the quinoline nitrogen is 7.29. At acidic lysosomal pH between 4-5.5, nearly 100% of chloroquine is doubly protonated, giving the molecule a 2+ charge, making it strongly hydrophilic, membrane-impermeable, and thus trapped in Acidic organelles.

[0187] A quantitative treatment of this trapping phenomenon can be obtained by examining the octanol-water partition coefficient log D of a drug, which describes the relative partition properties of all forms of a compound at different pH. For a given pH, compounds with positive logD are relatively lipophilic and more membrane permeable, while compounds with negative logD are hydrophilic and less membrane permeable.

[0188] exist Figures 1A-1B The...

Embodiment 2

[0194] Example 2: QR2 Inhibitor Synthesis and Characterization.

[0195]

[0196] A suspension of 4,7-dichloroquinoline (2.0 g, 10.2 mmol) in aqueous methylamine (40% 20 mL 260 mmol, 26 equiv) was heated in a microwave vessel at 90 °C (initial power setting 150 W) 2 hours. by TLC (2% MeOH / CH 2 Cl 2 ) analysis of the reaction mixture indicated complete consumption of starting material. The reaction mixture was treated with H 2 O (100 mL) was diluted, and the insoluble material was collected under vacuum. filter cake with H 2 O washed and dried in vacuo to give the pure product as a white microcrystalline solid (1.8 g, 92%). 1 H NMR (DMSO- d 6 , 300 MHz) δ 8.40 (d, J = 5.1 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.77(s, 1H), 6.38 (d, J = 5.4 Hz, 1H), 2.86 ( d, J = 5.4 Hz, 3H). ESIMS: m / z = 193[(M+H) + ].

[0197]

[0198] General procedure for 7-substituted-4-(pyridin-3-yl)-methylaminoquinolines. A mixture of 7-substituted-4-chloroquinoline (5.1 mmol), 3-aminome...

Embodiment 3

[0203] Example 3: Comparative testing of QR2 inhibitors.

[0204]

[0205] Table 1: Comparative ICs 50 data.

[0206] IC 50 (µM)

standard deviation

QR2 I-44 7.51 0.66 Compound 1 7.23 1.51 Compound 2 15.50 4.84 Chloroquine 70.92 5.27

[0207] We investigated the neuroprotective potential of QR2I-44 in a closed head injury (TBI) mouse model (Laskowitz et al., “Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumaticbrain injury murine model” , Sci. Rep. 2017 Apr 21;7:46461; Laskowitz et al., “Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic.” Journal of Neurotrauma 2010m 27:1983-1995). The closed head impact model results in damage to selectively vulnerable neurons in the cortex, basal ganglia, and hippocampus, induces diffuse axonal damage, and results in measurable vestibular ...

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Abstract

Provided herein according to some embodiments is a compound of Formula (I): [Formula], or a pharmaceutically acceptable salt or prodrug thereof. Compositions comprising the compound, and uses thereof for inhibiting the activity of quinone reductase-2, as well as in methods of treatment, are also provided.

Description

Background technique [0001] Aminoquinolines, modeled after chloroquine (CQ) and hydroxychloroquine (HQ), are quinone reductase 2 (QR2) inhibitors that were originally developed for the treatment of malaria but were subsequently found to have therapeutic efficacy for other indications, so Said indications include inter alia autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Singer et al., "Update on immunosuppressive therapy," Curr. Opin. Rheumatol. 1998, 10:169-173; Wallace, "The use of chloroquine and hydroxychloroquine for non-infectious conditions other than rheumatoid arthritis or lupus: a critical review," Lupus 1996, 5 Suppl 1:S59-64. In SLE and RA, aminoquinolines are the mainstay of first-line treatment and are often used in combination with other drugs. Aminoquinolines not only improve the signs and symptoms of SLE and RA, but also have beneficial effects on lipid metabolism and reduce the occurrence of thrombosis. Simi...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/517
CPCC07D401/12Y02A50/30
Inventor C·D·拉斯科拉D·T·拉斯科维茨
Owner DUKE UNIV
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