To discover a novel series of potent inhibitors of enteropeptidase, a membrane-bound serine protease localized to the duodenal brush border, 4-guanidinobenzoate derivatives were evaluated with minimal systemic exposure. The 1c docking model enabled the installation of an additional carboxylic acid moiety to obtain an extra interaction with enteropeptidase, yielding 2a. The oral administration of 2a significantly elevated the fecal protein output, a pharmacodynamic marker, in diet-induced obese (DIO) mice, whereas subcutaneous administration did not change this parameter. Thus, systemic exposure of 2a was not required for its pharmacological effects. Further optimization focusing on the in vitro IC₅₀ value and T_1/2, an indicator of dissociation time, followed by enhanced in vivo pharmacological activity based on the ester stability of the compounds, revealed two series of potent enteropeptidase inhibitors, a dihydrobenzofuran analogue ((S)-5b, SCO-792) and phenylisoxazoline (6b), which exhibited potent anti-obesity effects despite their low systemic exposure following their oral administration to DIO rats.

中文翻译：

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新型系列 4-胍基苯甲酸酯衍生物的设计、合成和生物学评价，作为低全身暴露量的肠肽酶抑制剂，用于治疗肥胖症

为了发现一系列新的肠肽酶强效抑制剂，一种定位于十二指肠刷状缘的膜结合丝氨酸蛋白酶，以最小的全身暴露评估了 4-胍基苯甲酸酯衍生物。1c对接模型能够安装额外的羧酸部分以获得与肠肽酶的额外相互作用，从而产生2a。在饮食诱导的肥胖 (DIO) 小鼠中，口服2a显着提高了粪便蛋白输出（一种药效学标志物），而皮下给药并未改变该参数。因此，2a的药理作用不需要全身暴露。进一步优化体外IC ₅₀值和T _1/2，解离时间的指标，然后基于化合物的酯稳定性增强的体内药理活性，揭示了两个系列的强效肠肽酶抑制剂，二氢苯并呋喃类似物 ( ( S )-5b， SCO-792 ) 和苯基异恶唑啉 ( 6b )，尽管它们在 DIO 大鼠口服给药后全身暴露量较低，但仍表现出有效的抗肥胖作用。