Discovery of Gut-Targeted GPR40 Agonist K‑757 and GPR119 Agonist K‑833, a Combination Treatment for Metabolic Disorders

Bariatric surgery provides long-term and robust weight
loss in
most patients. One leading hypothesis for this profound efficacy focuses
on the increased activation of gut enteroendocrine cells (EECs), resulting
in enhanced secretion of satiety hormones. We describe herein an approach
using a combination of gut-targeted small molecules to stimulate intestinal
nutrient receptors and mirror some of the hormone effects of bariatric
surgery. In preclinical studies, administration of GPR40 agonist K-757
in combination with GPR119 agonist K-833 resulted in robust increases
in the level of circulating hormones. In initial clinical studies,
pharmacokinetics and pharmacodynamics for each molecule were characterized
and largely recapitulated the effects of the individual compounds
in mice.

减肥手术（Bariatric Surgery）可使大多数患者实现长期且强效的体重减轻。针对该术式突出疗效的一项主流假说，聚焦于肠道内分泌细胞（gut enteroendocrine cells, EECs）的激活增强，进而提升饱腹激素的分泌水平。本文阐述了一种联合使用肠道靶向小分子的研究策略，通过刺激肠道营养受体，模拟减肥手术的部分激素效应。在临床前研究中，联合给予GPR40激动剂K-757与GPR119激动剂K-833，可显著升高循环激素水平。在初步临床研究中，我们对两种分子的药代动力学与药效动力学特征进行了表征，其作用效果基本重现了两种单体化合物在小鼠体内的效应。