Current status of GPR40/FFAR1 modulators in medicinal chemistry (2016–2019): a patent review

ABSTRACT

Introduction: The activation of free fatty acid receptor 1 (FFAR1) induces insulin secretion in a glucose-dependent manner, and thereby is considered as an attractive anti-diabetic target. The clinical studies provided a lot of evidence that FFAR1 agonists improved glucose control in T2DM without the risk of hypoglycemia. The field of FFAR1 agonists is extremely competitive with many patent applications filed in recent years identifying potent candidates.

Area covered: The present review summarizes patent applications (2016–2019) filing for FFAR1 modulators, including FFAR1 partial/full agonists, atypical agonists, and multiple target agonists, along with in vitro and in vivo evaluation.

Expert opinion: The clinical studies of FFAR1 agonists have proved their potential for the improvement of glucose control. However, there are a few issues still to be solved in this field since TAK-875 terminated in Phase III studies due to liver toxicity. The biggest challenge on the development of FFAR1 agonists may not be the identification of a highly potent compound, but finding out the exact mechanisms of hepatotoxicity and avoid it. Moreover, the further exploration of chemical spaces on FFAR1 full agonists and multi-targeted agonists, as well as corresponding clinical studies, will be expected and might open up new directions in this field.

KEYWORDS:

• Free fatty acid receptor 1
• hypoglycemia
• insulin
• structure-activity relationship
• type 2 diabetes

Article highlights

• FFAR1 is a promising target in glucose-dependent insulin secretion, and clinical proof-of-concept verified that FFAR1 agonists achieve therapeutic endpoint of glucose control in T2DM.

• The review covers the recent progress (2016–2019) in the patent applications of FFAR1 modulators, along with in vitro and in vivo evaluation as well as therapeutic applications.

• Four research directions have been pursued in identifying FFAR1 modulators, including FFAR1 partial/full agonists, atypical agonists, and multiple target agonists.

• The biggest challenge on the development of FFAR1 agonists may not be the identification of a highly potent compound, but find out the exact mechanisms of hepatotoxicity and avoid it.

• Results from clinical studies are needed to clarify the potential of new generation FFAR1 modulators, especially for FFAR1 full agonists.

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.

Reviewer disclosures

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

Additional information

Funding

This study was supported by the National Natural Science Foundation of China [Grant 81803341], the Natural Science Foundation of Guangdong Province, China [Grant 2018A030313445], the Guangdong Basic and Applied Basic Research Foundation [Grant 2019A1515011036], the Innovative strong school project of Guangdong Pharmaceutical University [Grant 2018KTSCX111], the National Science and Technology Major Project [2017ZX09101001], the projects of Guangzhou key laboratory of construction and application of new drug screening model systems [No. 201805010006] and Key Laboratory of New Drug Discovery and Evaluation of ordinary universities of Guangdong province [No. 2017KSYS002], the Innovation Team Projects in Universities of Guangdong Province [No. 2018KCXTD016].