Discovery of novel benzomorpholine derivatives as potent URAT1 inhibitors with hypouricemic effects

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-14 DOI:10.1016/j.bmcl.2025.130342

Yongcheng Wang , Lei Zhang , Mengjie Shao , Xianxin Hou , Ying Yang , Yifan Yang , Fei Ye , Xuechen Li , Zhiyan Xiao

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Abstract

Urate transporter 1 (URAT1) is a clinically validated therapeutic target for hyperuricemia and gout. To obtain structurally novel URAT1 inhibitors, a series of benzomorpholine derivatives were designed by adopting a pharmacophore guided molecular hybridization strategy. Most compounds potently inhibit the human URAT1 in HEK293 cells, and the most active compound 7 exhibited an IC₅₀ of 0.72 μM, which was much more potent than Lesinurad and comparable to Benzbromarone. The possible interaction mode of compound 7 with URAT1 was revealed by molecular modeling. Cell viability assays indicated that compound 7 was less cytotoxic than Benzbromarone in Hep-G2 cells. The urate-lowering effects of compounds 1 and 7 were confirmed in two different hyperuricemia mouse models, and no obvious toxicity was observed in the treated mice. The results provide new chemical prototypes for urate-lowering drug discovery targeting URAT1.

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发现新的苯并噻吩啉衍生物作为具有降尿酸作用的URAT1抑制剂。

尿酸转运蛋白1 （URAT1）是临床证实的治疗高尿酸血症和痛风的靶点。为了获得结构新颖的URAT1抑制剂，采用药效团引导的分子杂交策略设计了一系列苯并噻吩啉衍生物。大多数化合物在HEK293细胞中对人URAT1有较强的抑制作用，其中活性最高的化合物7的IC50值为0.72 μM，其抑制作用远高于Lesinurad，与苯溴马隆相当。通过分子模拟揭示了化合物7与URAT1可能的相互作用模式。细胞活力测定表明，化合物7对Hep-G2细胞的细胞毒性低于苯溴马龙。化合物1和7的降尿酸作用在两种不同的高尿酸血症小鼠模型中得到证实，对治疗小鼠没有明显的毒性作用。研究结果为发现靶向URAT1的降尿酸药物提供了新的化学原型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.