Small-Molecule Modulators of GPR40 (FFA1)

The free fatty acid receptor 1 (FFAR1/GPR40) amplifies glucose-dependent insulin secretion; therefore, it has attracted widespread attention as a promising antidiabetic target. Current clinical proof of concept also indicates that FFAR1 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus (T2DM) without the hypoglycemic risk. Thus, many pharmaceutical companies and academic institutes are competing to develop FFAR1 agonists. However, several candidates have been discontinued in clinical trials, often without reporting the underlying reasons. Herein, we review the challenges and corresponding strategies chosen by different medicinal chemistry teams to improve the physicochemical properties, potency, pharmacokinetics, and safety profiles of FFAR1 agonists, with a brief introduction to the biology and pharmacology of related targets.

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“…and Brown et al. reviewed separately the development of FFAR1 agonists and related clinical data . In 2016, Li et al.…”

Section: Introductionmentioning

confidence: 99%

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

Xue

Huang

et al. 2017

Medicinal Research Reviews

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“…GPR40 is a G-protein-coupled receptor, primarily expressed in pancreatic islets β-cells and enteroendocrine L-cells that possess the ability to modulate several metabolic defects when activated. Medium- to long-chain fatty acids bind to and elicit GPR40 to increase insulin secretion from β-cells and increased secretion of the gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). − …”

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confidence: 99%

“…Agonists of GPR40 present low risk of hypoglycemia and have been considered by multiple groups leading to the discovery of multiple clinical candidates. − These clinical candidates, such as AMG 837 ( 1 ), are all partial agonists of GPR40. We previously described the discovery of 1 , − which demonstrates antidiabetic activity in rodent models without exhibiting hypoglycemia.…”

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confidence: 99%

Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates

Brown

Dransfield

Vimolratana

et al. 2018

ACS Med. Chem. Lett.

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GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (), a full agonist of GPR40. Herein, we present further structure-activity relationships progressing from AM-1638 () to AM-6226 () that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 () is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control.

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Molecular Complexity as a Driver for Chemical Process Innovation in the Pharmaceutical Industry

et al. 2019

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A Perspective of our work in the development of innovative synthetic methods within the discipline of Process Research and Development is presented. Through an overview of some of the programs that we have worked on during the past decade, we have selected cases studies to illustrate the challenges faced in development of robust chemical processes for molecules on a multi-kilogram scale. The examples have been selected to demonstrate the innovative chemistry being developed within our laboratories with a focus on fragment design, asymmetric synthesis, new synthetic reagents, and the methods that have allowed us to deliver cost-effective syntheses under reduced timelines in an increasingly competitive environment. The technical challenges are presented in the context of molecule complexity that while increasing in the portfolio of small molecules being developed inspires us to deliver new solutions. Overall, our goal is to highlight the exciting work that can be done within our field to support the discovery and delivery of medicines to patients.

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Small-Molecule Modulators of GPR40 (FFA1)

Cited by 3 publications

References 24 publications

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates

Molecular Complexity as a Driver for Chemical Process Innovation in the Pharmaceutical Industry

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