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Benzimidazole derivatives and uses thereof

一种药物、组合物的技术，应用在苯并咪唑衍生物及其用途领域，能够解决限制先导化合物进展、阻碍早期临床评价等问题

Inactive Publication Date: 2016-02-17
WHITEHEAD INST FOR BIOMEDICAL RES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When phenotypic screens are unbiased, the daunting challenge of deciphering the mechanism of action can limit the progress of lead compounds by hampering target-directed medicinal chemistry and early clinical evaluation of target efficacy

Method used

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  • Benzimidazole derivatives and uses thereof
  • Benzimidazole derivatives and uses thereof
  • Benzimidazole derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0287] Embodiment 1. The preparation of compound

[0288] Compounds of formula (I) can be prepared by the synthetic sequence shown in Scheme 1 below. Alternatively, compounds of formula (I) may be synthesized by other methods described herein.

[0289]

[0290] Scheme 1. Exemplary Synthesis of Compounds of Formula (I)

[0291] Compound ABI in the initial screen was purchased from ChemDiv (K783-0286). The following syntheses were carried out according to the scheme below.

[0292] O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 99%) was purchased from Oakwood Products, Inc., and iron powder (99 %, 325 mesh) was purchased from Acros Organics. All other starting materials and solvents were purchased from Aldrich Chemical Co. or Alfa Aesar, and all reagents were used as received. The mixture was purified by flash chromatography using Silicycle SiliaFlashP60 (230-400 mesh) silica gel. All new compounds start with 1 HNMR, 13 Characterized by ...

Embodiment 2

[0303] Example 2. High Throughput Small Molecule Screening

[0304] Taking advantage of the ease of yeast culture and the ability to simultaneously induce the expression of toxic proteins that strongly inhibit growth, 190,000 different compounds were screened for restoring the growth of cells expressing the ND-associated protein TDP-43 (6). Compound ABI (FIG. 1A), identified as having modest potency against TDP-43, was demonstrated to be more potent and efficacious against α-syn (FIG. 1B). However, ABI was not effective against other ND-associated proteins, including htt72Q, FUS / TLS and Aβ peptide (Fig. IB). Thus, rather than targeting a common feature of misfolded protein toxicity, rescue reflects the targeting of ABI (and the ability to reduce TDP-43 levels) to specific α-syn-associated pathologies.

[0305] ABI was found to be able to reverse several key pathogenic features of α-syn toxicity. First, ABI prevents the accumulation of cytoplasmic α-syn foci, which are the ac...

Embodiment 3

[0306] Example 3. Screening of chemical genes

[0307] overexpression screening

[0308] Overexpression screening was performed by using pooled FlexGene libraries (35) transformed into WT yeast impairing drug efflux. Frozen aliquots of pooled yeast stocks were thawed in SGalUra supplemented with 30 mL of 0.05% glucose and grown at 30°C for approximately 8 hours. During this period, the medium was increased approximately 0.5-1 fold. Then, dilute the yeast to OD in SGalUra 600 is 0.0005, which corresponds to approximately 20-fold coverage of diversity in the library and 40 μM ABI2. After approximately 3 days of growth, apparent colony growth in 384-well plates was restored and verified individually. Plasmids were recovered and amplified in E. coli and sequenced by using the Yeast Plasmid Isolation Kit (ZymoResearch). The resulting sequence was then queried with BlastN (NCBI) and a reliable ORF was confirmed.

[0309] Transposon (Tn7) Screening

[0310] Screening based on ...

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Abstract

The present invention provides novel compounds of formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. The present invention also provides methods and kits using the inventive compounds and pharmaceutical compositions for treating and / or preventing diseases associated with protein aggregation, such as amyloidoses (e.g., Parkinson's disease and Alzheimer's disease), treating and / or preventing neurodegenerative diseases, treating and / or preventing diseases associated with Tar DNA binding protein 43 kDa, reducing or preventing protein aggregation, and / or modulating E3 ubiquitin ligase in a subject in need thereof.

Description

[0001] related application [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application U.S.S.N. 61 / 794,870, filed March 15, 2013, which is incorporated herein by reference. [0003] governmental support [0004] This invention was made with US Government support under National Institute of Health Grant No. GM58160. The US Government has certain rights in this invention. Background of the invention [0005] Due to an incomplete understanding of the molecular perturbations that cause the disease, and a limited theoretical reserve of robust model systems, it has not been possible to successfully develop neurodegenerative diseases (ND) for common and progressive neurodegenerative diseases (ND), such as Parkinson's disease (PD) and Alzheimer's disease. Disease-modifying treatments for Alzheimer's disease (AD). These limitations, combined with the generally expected limitations of "druggable" proteomes, constitute a major challenge for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N37/18A01N43/40A01N43/50
CPCA61K31/4184A61K45/06A61K31/4439C07D235/08C07D235/16C07D401/12C07D403/04C07D405/04C07D409/12A61P21/02A61P25/00A61P25/16A61P25/28A61K2300/00
Inventor S.L.林奎斯特S.L.布赫瓦尔德D.塔迪夫N.朱伊
Owner WHITEHEAD INST FOR BIOMEDICAL RES
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