Benzylamino-oxoethyl benzamide analogs and methods of use

Abstract

Benzylamino-oxoethyl benzamide compounds for use in treating diseases and conditions associated with abnormal cell function related to endoplasmic reticulum (ER) stress. For example, the compounds can be used as suppressors of ER stress-induced pancreatic β-cell dysfunction and death, for example in the treatment of Type 1 and Type 2 diabetes. The compounds can also be used in treatments for chronic heart disease, neurodegenerative diseases, retinal degeneration, and other metabolic disorders associated with ER stress.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority under 35 U.S.C. § 119(e) to U.S. Ser. No. 62 / 726,634, filed Sep. 4, 2018, the entirety of which is hereby expressly incorporated by reference herein.GOVERNMENT SUPPORT[0002]This invention was made with government support under Grant numbers GM103636 and DK108887 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND[0003]The endoplasmic reticulum (ER) has key roles in synthesis, folding and maturation of secreted transmembrane proteins. Upon translation, secretory, luminal and membrane proteins are translocated into the lumen of the ER where they are covalently modified and attain their proper folding. A balance between the ER protein loading and its folding capacity must be established to maintain the proper function of the ER. However, pathophysiological stimuli can disrupt this ER homeostasis, resulting in an accumulation of unfolded or misfold...

AI Technical Summary

Benefits of technology

[0005]Recent reports of chemical chaperones such as 4-phenyl butyrate (PBA) and tauroursodeoxycholic acid (TUDCA) have been shown to have an effect on ER stress modulation and antidiabetic activity in T2D animal models. However, because of their low efficacy, large doses are needed for any therapeutic treatment, which makes it unlikely that these agents can be used for the treatment for human patients due to the increased toxicity. Agents which are effective in treating ER stress-related conditions at low doses would be highly desirable. It is to this need that the present disclosure is directed.

Problems solved by technology

However, pathophysiological stimuli can disrupt this ER homeostasis, resulting in an accumulation of unfolded or misfolded proteins in the ER, a condition known as ER stress.

Under chronic or severe ER stress, however, the UPR often fails to adequately resolve ER stress and instead activates the expression of ER stress-specific pro-apoptotic genes such as the transcription factor C / EBP-homologous protein (CHOP), eventually leading to cell death.

Type 2 Diabetes (T2D), a chronic condition of hyperglycemia, is a pervasive threat to health and a burden on the healthcare system in the United States.

However, because of their low efficacy, large doses are needed for any therapeutic treatment, which makes it unlikely that these agents can be used for the treatment for human patients due to the increased toxicity.

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