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Imidazopyridine and Oxazolopyridine Derivatives and Analogs Thereof, Methods of Preparation Thereof, Methods of HIF-2A Pathway Inhibition, and Induction of Ferroptosis

Active Publication Date: 2022-09-08
KUDA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent is about compounds that can stop the production of a protein called HIF-2α, which is associated with disorders such as tumors and iron accumulation. These compounds do this by targeting a protein called iron sulfur cluster assembly 2 (ISCA2). This prevents the uptake of iron and promotes iron deprivation, which leads to cell death. Therefore, these compounds can be used to treat disorders associated with HIF-2α and iron or lipid accumulation.

Problems solved by technology

Additionally, the compounds interfere with cellular iron metabolism creating a situation of ‘apparent’ iron deprivation (given by elevated IRP2 and decreased FTH1) despite elevated iron levels within cells, which promotes iron-dependent cell death, or ferroptosis.

Method used

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  • Imidazopyridine and Oxazolopyridine Derivatives and Analogs Thereof, Methods of Preparation Thereof, Methods of HIF-2A Pathway Inhibition, and Induction of Ferroptosis
  • Imidazopyridine and Oxazolopyridine Derivatives and Analogs Thereof, Methods of Preparation Thereof, Methods of HIF-2A Pathway Inhibition, and Induction of Ferroptosis
  • Imidazopyridine and Oxazolopyridine Derivatives and Analogs Thereof, Methods of Preparation Thereof, Methods of HIF-2A Pathway Inhibition, and Induction of Ferroptosis

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0327]Synthesis Schemes, Methods and Procedures:

Dimethyl (5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)carbonimidodithioate (S1)

[0328]To a flame-dried, 100 mL round bottom flask equipped with a magnetic stir bar was added 5-(4-fluorophenyl)-1,3,4-oxadiazol-2-amine (1.00 g, 5.58 mmol) and DMF (10 mL). The reaction was cooled to 0° C., and aqueous NaOH (20 M, 0.31 mL) was added dropwise. Upon complete addition, the reaction was allowed to stir for 10 minutes followed by dropwise addition of CS2 (0.62 mL). The resulting solution was allowed to warm to room temperature over a period of 30 minutes. The flask was again cooled to 0° C., and iodomethane (1.6 g) was added dropwise. Upon addition, a yellow precipitate formed. The reaction was allowed to proceed for 30 minutes, and completion was confirmed by LC-MS. The reaction contents were then poured an Erlenmeyer flask with 50 mL of H2O, and the resulting precipitate was collected by vacuum filtration. The yellow precipitate was recrystallized...

example 2

[0399]Hypoxia-Responsive Element-Driven Luciferase Screens to Identify Inhibitors of HIF-2α Transcriptional Activity.

[0400]Screens for inhibitory activity of compounds described herein were performed using 786-0 CCRCC cells that stably express HRE-Luc: 5 copies of the hypoxia-responsive element (HRE) fused to the pGL3 luciferase reporter (Promega Corp, Madison Wis.). 786-0 cells are pVHL deficient and thus constitutively express HIF-2α independently of cellular oxygen tension (Maxwell, Wiesener et al. 1999). Since 786-0 cells lack HIF-1α, HRE-driven luciferase activity is primarily HIF-2α driven, and has been previously validated (Koh, Lemos et al. 2011). Cells were maintained at log phase growth in Dulbecco's minimal essential media (DMEM) with 10% FBS in a humidified incubator at 37° C. with 5% CO2. For screening assays, cells were seeded at a density of 4,000 cells in 50 μl of complete media / well in quadruplicate wells / point in a 96-well plate. 24 hours later, 50 μl of a 2× conce...

example 3

[0403]Western Blots to Determine Impact of Compounds on HIF-2α and Cellular Iron-Sensing Machinery.

[0404]Western blots were performed to determine the effects of the compounds on levels of HIF-2α and other relevant proteins. 786-0 (pVHL deficient clear cell kidney cancer cells) were purchased from ATCC were plated at 1×10E5 cells / well in 2 ml DMEM with 10% FBS / well in 6-well tissue culture plates. Cells were allowed to adhere overnight in a humidified incubator at 37° C. with 5% CO2, after which the appropriate concentrations of compounds in DMSO were added. DMSO concentrations were kept constant in all wells. After 24 hour's exposure to the compounds, cells were lysed and subjected to western blotting according to standard protocols (Polek, Talpaz et al. 2003). Antibodies for HIF-2α and Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) were purchased from Cell Signaling Technology (Danvers, Mass.), whereas antibodies to iron responsive element binding protein 2 (IRP2) and Glutathion...

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Abstract

Novel substituted imidazopyridine and oxazolopyridine compounds that are useful as inhibitors of HIF-2α and inducers of ferroptosis through perturbations in iron metabolism, synthetic methods for making said compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions to treat disorders associated with dysfunction of HIF-2α or iron metabolism.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of and priority to U.S. Prov. Pat. App. Ser. No. 62 / 805,699 entitled “Imidazopyridine and oxazolopyridine derivatives and analogs thereof, methods of preparation thereof, methods of HIF-2α pathway inhibition, and induction of ferroptosis,” filed Feb. 14, 2019, the entirety of which is incorporated by reference herein.STATEMENT OF FEDERAL FUNDING[0002]This invention was in part funded by grants from the National Institutes of Health, National Institute on Drug Abuse 1R03DA033980 and the National Cancer Institute Small Business Innovation Research Program R43CA217385. The government has certain rights in the invention.BACKGROUND1. Technical Field[0003]The present disclosure relates to novel compounds and more particularly to imidazopyridine and oxazolopyridine derivative and analogs thereof as well as methods of making and using such compounds.2. Related Technology[0004]Hypoxia provides the required extra...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D417/12C07D471/04C07D498/04C07D487/04C07D513/04A61P35/00
CPCC07D417/12C07D471/04C07D498/04C07D487/04C07D513/04A61P35/00
Inventor LIU, XIAOHUIKOH, MEI YEE
Owner KUDA THERAPEUTICS INC
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