A patent review on aldehyde dehydrogenase inhibitors: an overview of small molecule inhibitors from the last decade

ABSTRACT

Introduction

Physiological and pathophysiological effects arising from detoxification of aldehydes in humans implicate the enzyme aldehyde dehydrogenase (ALDH) gene family comprising of 19 isoforms. The main function of this enzyme family is to metabolize reactive aldehydes to carboxylic acids. Dysregulation of ALDH activity has been associated with various diseases. Extensive research has since gone into studying ALHD isozymes, their structural biology and developing small-molecule inhibitors. Novel chemical strategies to enhance the selectivity of ALDH inhibitors have now appeared.

Areas covered

A comprehensive review of patent literature related to aldehyde dehydrogenase inhibitors in the last decade and half (2007–2022) is provided.

Expert Opinion

Aldehyde dehydrogenase (ALDH) is an important enzyme that metabolizes reactive exogenous and endogenous aldehydes in the body through NAD(P)±dependent oxidation. Hence this family of enzymes possess important physiological as well as toxicological roles in human body. Significant efforts in the field have led to potent inhibitors with approved clinical agents for alcohol use disorder therapy. Further clinical translation of novel compounds targeting ALDH inhibition will validate the promised therapeutic potential in treating many human diseases.

The scientific/patent literature has been searched on SciFinder-n, Reaxys, PubMed, Espacenet and Google Patents. The search terms used were ‘ALDH inhibitors’, ‘Aldehyde Dehydrogenase Inhibitors’

KEYWORDS:

• ALDH
• anti-dipsotropic
• inflammatory diseases
• cancer stem cells
• addiction

Article highlights

• Since the discovery and elucidation of the role of ALDH2 in alcohol metabolism, research led to the development of ALDH2i as alcohol-aversion agents

• While initial research was focused on irreversible, nonselective ALDH, the last decade has witnessed several drug-discovery campaigns to develop isozyme-specific ALDH inhibitors

• The field is still evolving with increasing number of approaches appearing to target selective ALDH enzyme inhibition in various diseases

• Novel agents based on ALDH inhibition are in clinical trials although no new agents have been approved in the last decade

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by intramural funds from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to M.R.I.(ZIA AA000360-03).