Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

The free fatty acid
receptor 4 (FFA4 or GPR120) has appeared as
an interesting potential target for the treatment of metabolic disorders.
At present, most FFA4 ligands are carboxylic acids that are assumed
to mimic the endogenous long-chain fatty acid agonists. Here, we report
preliminary structure–activity relationship studies of a previously
disclosed nonacidic sulfonamide FFA4 agonist. Mutagenesis studies
indicate that the compounds are orthosteric agonists despite the absence
of a carboxylate function. The preferred compounds showed full agonist
activity on FFA4 and complete selectivity over FFA1, although a significant
fraction of these noncarboxylic acids also showed partial antagonistic
activity on FFA1. Studies in normal and diet-induced obese (DIO) mice
with the preferred compound 34 showed improved glucose
tolerance after oral dosing in an oral glucose tolerance test. Chronic
dosing of 34 in DIO mice resulted in significantly increased
insulin sensitivity and a moderate but significant reduction in bodyweight,
effects that were also present in mice lacking FFA1 but absent in
mice lacking FFA4.

游离脂肪酸受体4（free fatty acid receptor 4，FFA4 又称GPR120）已成为治疗代谢紊乱的极具潜力的研究靶点。目前，绝大多数FFA4配体均为羧酸类化合物，这类配体被认为可模拟内源性长链脂肪酸激动剂。本文报道了一类此前已公开的非酸性磺酰胺类FFA4激动剂的初步构效关系研究结果。诱变研究表明，尽管此类化合物不含羧酸基团，但它们仍属于正位激动剂。优选化合物对FFA4展现出完全激动活性，且对FFA1具备优异的选择性；不过其中相当一部分非羧酸类化合物同时对FFA1表现出部分拮抗活性。针对优选化合物34的研究显示，在口服葡萄糖耐量试验中，对正常小鼠及饮食诱导肥胖（diet-induced obese，DIO）小鼠口服给药后，可改善其葡萄糖耐量。对DIO小鼠长期给予化合物34后，其胰岛素敏感性显著提升，体重出现中度但具有统计学意义的下降；这类效应在缺失FFA1的小鼠中依然存在，但在缺失FFA4的小鼠中则未出现。