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

Zheng Li1, Xue Xu2, Wenlong Huang1,3

  • 1Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, P.R., China.

Medicinal Research Reviews
|March 23, 2017
PubMed

Insights

Free fatty acid receptor 1 (FFAR1) agonists show promise for treating type 2 diabetes by enhancing insulin secretion. This review explores strategies to overcome challenges in developing effective FFAR1-based antidiabetic therapies.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Endocrinology

Background:

  • Free fatty acid receptor 1 (FFAR1/GPR40) is a key target for type 2 diabetes mellitus (T2DM) treatment, enhancing glucose-dependent insulin secretion.
  • FFAR1 agonists have demonstrated potential for T2DM therapy without causing hypoglycemia, attracting significant research interest.
  • Despite promising preclinical data, several FFAR1 agonist candidates have faced clinical trial discontinuations, necessitating a deeper understanding of development challenges.

Purpose of the Study:

  • To review the challenges encountered in developing FFAR1 agonists for T2DM.
  • To outline strategies employed by medicinal chemistry teams to optimize FFAR1 agonist properties.
  • To provide insights into improving physicochemical, pharmacokinetic, and safety profiles of FFAR1 agonists.

Main Methods:

  • Literature review of FFAR1 agonist development.
  • Analysis of medicinal chemistry strategies for property optimization.
  • Discussion of biological and pharmacological aspects of FFAR1 and related targets.

Main Results:

  • Identified key challenges in FFAR1 agonist development, including physicochemical limitations, pharmacokinetic variability, and safety concerns.
  • Highlighted diverse strategies used to enhance potency, selectivity, and drug-like properties of FFAR1 agonists.
  • Summarized approaches to mitigate potential adverse effects and improve clinical translatability.

Conclusions:

  • Overcoming development hurdles requires a multifaceted medicinal chemistry approach.
  • Optimizing FFAR1 agonists necessitates balancing potency, pharmacokinetics, and safety.
  • Continued innovation in FFAR1 agonist design is crucial for advancing T2DM treatment options.
Keywords:
GLP-1GPR40free fatty acidtoxicitytype 2 diabetes

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