游离脂肪酸受体 1（FFAR1）作为 2 型糖尿病的新兴治疗靶点：最新进展与现存挑战。
Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges.
机构信息
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, P.R., China.
Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, P.R., China.
出版信息
Med Res Rev. 2018 Mar;38(2):381-425. doi: 10.1002/med.21441. Epub 2017 Mar 22.
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.
游离脂肪酸受体 1（FFAR1/GPR40）可增强葡萄糖依赖性胰岛素分泌；因此，它作为一种有前途的抗糖尿病靶标引起了广泛关注。目前的临床概念验证也表明，FFAR1 激动剂在没有低血糖风险的情况下实现了治疗 2 型糖尿病（T2DM）的最初治疗终点。因此，许多制药公司和学术机构正在竞相开发 FFAR1 激动剂。然而，有几个候选药物在临床试验中被中止，而没有报告潜在的原因。在此，我们回顾了不同药物化学团队为改善 FFAR1 激动剂的理化性质、效力、药代动力学和安全性概况而选择的挑战和相应策略，并简要介绍了相关靶标的生物学和药理学。
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