TGR5 agonists for diabetes treatment: a patent review and clinical advancements (2012-present)

ABSTRACT

Introduction

A cell surface bile acid receptor TGR5 is expressed in various tissues, including the liver, kidney, intestine, and adrenal glands, causing its effect in each tissue to differ. A major role for TGR5 is to maintain blood sugar levels and increase in energy expenditure. These benefits make it a potential candidate for the treatment of type 2 diabetes, obesity, and other metabolic diseases.

Area covered

This paper highlights recent advances in the development of potent steroidal and non-steroidal TGR5 agonists and the peer-reviewed scientific articles that have led to understanding the structure-activity relationship for TGR5 agonists (2012–2020). The review also discusses the clinical progress made by some TGR5 agonists over the past eight years.

Expert opinion

In preclinical studies, TGR5 has been found to play a crucial role in GLP-1 secretion and has shown promise for weight loss, anti-diabetic outcomes etc. Semi synthetic and synthetic derivatives can be considered a potential avenue for discovering novel TGR5 agonists. Currently, few TGR5 agonists have reached the clinical trial stage, and, likely, soon novel TGR5 modulator will be discovered with fewer adverse effects. In silico studies can also be performed with various heterocyclic scaffolds to discover selective and safe TGR5 agonists.

KEYWORDS:

• G-protein-coupled receptor
• bile acid
• type 2 diabetes mellitus
• glucagon-like peptide-1
• structure-activity relationships
• TGR5 agonists

Funding

This paper was not funded.

Article highlights

• Diabetes, a metabolic disorder that is regarded as a major concern worldwide and is associated with various other health complications, such as obesity, cardiovascular problems, and eye disorders.

• TGR5 has been identified as a potential target for the treatment of type 2 diabetes mellitus and other metabolic disorders such as obesity through the regulation of GLP-1 secretion and the enhancement of energy expenditure in adipose tissues in recent years.

• This article summarizes the development of TGR5 agonists as described in the patents and literature since 2012.

• Several researchers and pharmaceutical companies are engaged in developing TGR5 ligands with greater potency, reduced risk of side effects, and gastrointestinal chemotypes targeted for use.

• A few compounds have entered clinical trials intending to develop a potent and safe TGR5 agonist in the future.

This box summarizes key points contained in the article.

Declaration of interest

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.