Bioorganic & Medicinal Chemistry Letters最新文献_第6页

Synthesis of dolutegravir derivatives modified by 1,2,3-triazole structure and their anti-inflammatory activity in LPS-induced BV2 cells 1,2,3-三唑结构修饰多替格拉韦衍生物的合成及其对lps诱导BV2细胞的抗炎活性

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-16 DOI: 10.1016/j.bmcl.2024.130076

Xixi Hou , Longfei Mao , Xuanwei Zhang , Xi Wang , Lan Wang , Jianji Wang

Given the promising anti-inflammatory activity of the HIV integrase inhibitor dolutegravir and the widespread use of the 1,2,3-triazole structure in anti-inflammatory drug development, this study aimed to enhance dolutegravir’s efficacy by introducing a 1,2,3-triazole group. As a result, four series of dolutegravir derivatives were synthesized. Screening these derivatives for anti-inflammatory activity in microglial cells revealed that compound 6k demonstrated the most potent anti-inflammatory effect without significant cytotoxicity. Specifically, 6k significantly reduced the transcription levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Additionally, 6k decreased the LPS-induced overproduction of inflammatory mediators such as nitric oxide (NO), IL-6, and TNF-α. Further investigation into the upstream inflammatory enzymes iNOS and COX-2 showed that 6k markedly reduced their transcription and protein levels. To elucidate the mechanism underlying the anti-inflammatory effects of dolutegravir derivatives, it was found that compound 6k modulates microglial inflammation by inhibiting the phosphorylation and nuclear translocation of signal transducer and activator of transcription 1/3 (STAT1/3). Moreover, acute toxicity testing in mice indicated that compound 6k exhibited low toxicity, suggesting its potential as a lead compound for the treatment of neuroinflammation.

鉴于HIV整合酶抑制剂dolutegravir具有良好的抗炎活性，以及1,2,3-三唑结构在抗炎药物开发中的广泛应用，本研究旨在通过引入1,2,3-三唑基团来增强dolutegravir的疗效。结果，合成了4个系列的地重韦衍生物。对这些衍生物在小胶质细胞中的抗炎活性进行筛选发现，化合物6k具有最有效的抗炎作用，且没有明显的细胞毒性。具体来说，6k显著降低了脂多糖（LPS）诱导的BV-2小胶质细胞中促炎细胞因子IL-1β、IL-6和TNF-α的转录水平。此外，6k减少了lps诱导的炎症介质如一氧化氮（NO）、IL-6和TNF-α的过量产生。对上游炎症酶iNOS和COX-2的进一步研究表明，6k显著降低了它们的转录和蛋白水平。为了阐明多替格拉韦衍生物抗炎作用的机制，我们发现化合物6k通过抑制信号转导因子和转录激活因子1/3 （STAT1/3）的磷酸化和核易位来调节小胶质细胞炎症。此外，小鼠急性毒性试验表明，化合物6k表现出低毒性，表明其可能作为治疗神经炎症的先导化合物。

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引用次数: 0

Design and evaluation of anaplastic lymphoma kinase degraders using a covalent fumarate handle 采用共价富马酸处理的间变性淋巴瘤激酶降解剂的设计和评价。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-15 DOI: 10.1016/j.bmcl.2024.130075

Namsik Yu , Ji-Eun Lee , Seulki Park , Su Kyeong Yun , Do Hyun Ryu , Jung-Ae Kim , Jeong-Hoon Kim , Jong Yeon Hwang

Targeted protein degradation has emerged as a novel therapeutic paradigm in drug discovery. Despite the FDA approval of anaplastic lymphoma kinase (ALK) inhibitors, the pursuit of compounds with enhanced potency and prolonged efficacy remains crucial to mitigate inevitable adverse effects. In this context, we endeavored to develop ALK degraders utilizing FDA-approved ALK inhibitors—crizotinib, ceritinib, brigatinib, and alectinib—as ALK binders, along with 4-methoxyphenylfumarate as a covalent handle to bind to RNF126 E3 ligase. Among the synthesized compounds, dALK-3—derived from brigatinib—efficiently induced the proteasomal degradation of EML4-ALK and exhibited a 10-fold superior anti-proliferative effect on H3122 cells compared to brigatinib. However, the enhanced anti-proliferative activity of dALK-3 was found to be independent of RNF126, a presumed potential E3 ligase, suggesting the need for investigation of other components within the ubiquitin–proteasome system. Our findings further support the potential application of the fumarate moiety as a binder for E3 ligases in targeted protein degradation.

靶向蛋白降解已成为药物发现的一种新的治疗范式。尽管FDA批准了间变性淋巴瘤激酶（ALK）抑制剂，但寻求具有增强效力和延长疗效的化合物对于减轻不可避免的不良反应仍然至关重要。在这种情况下，我们努力开发ALK降解剂，利用fda批准的ALK抑制剂——克唑替尼、塞瑞替尼、布加替尼和阿勒替尼——作为ALK结合剂，以及4-甲氧基苯基富马酸酯作为共价柄结合到RNF126 E3连接酶上。在合成的化合物中，布加替尼衍生的dalk -3有效诱导EML4-ALK的蛋白酶体降解，对H3122细胞的抗增殖作用比布加替尼强10倍。然而，研究发现dALK-3的抗增殖活性增强与RNF126（一种假定的潜在E3连接酶）无关，这表明需要研究泛素-蛋白酶体系统中的其他成分。我们的发现进一步支持富马酸片段作为E3连接酶在靶向蛋白质降解中的粘合剂的潜在应用。

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引用次数: 0

Development of 3-indolyl substituted phenyl pyrazolo-carboxamide hybrids as potential type II VEGFR-2 inhibitors and in vitro cytotoxicity studies 将 3-吲哚基取代的苯基吡唑-甲酰胺杂交化合物开发为潜在的 II 型血管内皮生长因子受体-2 抑制剂并进行体外细胞毒性研究。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-12 DOI: 10.1016/j.bmcl.2024.130070

Durgesh Gurukkala Valapil , Geetanjali Devabattula , Aman Singh Barahdia , Chandraiah Godugu , Nagula Shankaraiah

The progression of tumors is intricately linked to angiogenesis, the formation of new blood vessels, driven primarily by the release of growth factors such as Vascular Endothelial Growth Factor (VEGF). Targeting VEGF signaling through its receptor kinase (VEGFR-2) has emerged as a promising anti-angiogenic strategy for cancer therapy. In this study, we designed and synthesized a series of novel chemical entities based on 3-indolyl substituted phenyl pyrazole-carboxamides through docking studies upon considering the structure of sorafenib and its pattern of type II inhibition of VEGFR-2. Among the synthesized hybrids, 7b was able to significantly inhibit the growth of cancer cell lines, specifically against MCF-7 at 2.12 ± 0.19 μM. Compound 7b also efficiently inhibited VEGFR-2 kinase at a concentration of 2.83 ± 0.86 μM during the in vitro studies. Mechanistic studies revealed that 7b induced apoptosis evidenced by AO/EB, DAPI, and DCFDA staining, and its impact on the migratory ability of the cancer cells were also studied. These findings highlight the potential of 7b as a lead candidate for further development of anti-angiogenic therapies targeting VEGFR-2.

肿瘤的进展与血管生成密切相关，血管生成是指新血管的形成，主要由血管内皮生长因子（VEGF）等生长因子的释放驱动。通过血管内皮生长因子受体激酶（VEGFR-2）靶向血管内皮生长因子信号转导已成为一种很有前景的抗血管生成癌症治疗策略。在本研究中，我们考虑到索拉非尼的结构及其对 VEGFR-2 的 II 型抑制模式，通过对接研究设计并合成了一系列基于 3-吲哚基取代苯基吡唑-羧酰胺的新型化学实体。在合成的混合物中，7b 能够显著抑制癌细胞株的生长，特别是对 MCF-7 的抑制作用为 2.12 ± 0.19 μM。在体外研究中，化合物 7b 还能以 3.47 ± 0.13 μM 的浓度有效抑制血管内皮生长因子受体-2 激酶。机理研究显示，7b 可诱导细胞凋亡，这一点可通过 AO/EB、DAPI 和 DCFDA 染色来证明，同时还研究了它对癌细胞迁移能力的影响。这些发现凸显了 7b 作为进一步开发针对血管内皮生长因子受体 2 的抗血管生成疗法的候选药物的潜力。

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引用次数: 0

Neratinib derivative 7A induces apoptosis in colon cancer cells via the p53 pathway 奈拉替尼衍生物 7A 通过 p53 通路诱导结肠癌细胞凋亡

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-12 DOI: 10.1016/j.bmcl.2024.130069

Zhi-Yu Liu , Ruo-Tong Liu , Wen-Hao Cheng , Bo-Yu Zhang , Xing-Yu Zhang , Ying Zhou , Xiao-Qing Ye , Chun-Yun Zhou , Xiu-Jun Wang , Qian Sun , Jing Ji

Colorectal cancer remains a significant health threat, with its incidence continuously rising, underscoring the urgent need for the development of new therapeutic agents. In our previous research, we identified 7A, a derivative of Neratinib, as having pronounced antitumor activity. However, its specific effects and mechanisms in colorectal cancer have not been thoroughly investigated. Therefore, this study employed in vivo and in vitro experiments, utilizing techniques such as RNA sequencing, Western blotting, and PCR, to provide a comprehensive analysis of 7A’s mechanism of action in colorectal cancer. The results indicate that 7A induces DNA damage and activates the P53 pathway, thereby promoting apoptosis in colorectal cancer cells. Additionally, 7A treatment significantly reduced angiogenesis and tumor weight. Our findings suggest that 7A, a Neratinib derivative, holds promise as a novel candidate for colorectal cancer therapy.

结肠直肠癌仍然是一个严重的健康威胁，其发病率持续上升，因此迫切需要开发新的治疗药物。在之前的研究中，我们发现奈拉替尼的衍生物 7A 具有明显的抗肿瘤活性。然而，它在结直肠癌中的具体作用和机制尚未得到深入研究。因此，本研究采用体内和体外实验，利用 RNA 测序、Western 印迹和 PCR 等技术，全面分析了 7A 在结直肠癌中的作用机制。结果表明，7A 能诱导 DNA 损伤并激活 P53 通路，从而促进结直肠癌细胞凋亡。此外，7A 还能显著减少血管生成和肿瘤重量。我们的研究结果表明，7A（一种奈拉替尼衍生物）有望成为结直肠癌治疗的新型候选药物。

引用次数: 0

Deep mutational scanning-guided design of a high-affinity helix–loop–helix peptide targeting G-CSF receptor 靶向G-CSF受体的高亲和螺旋-环-螺旋肽的深度突变扫描引导设计。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-10 DOI: 10.1016/j.bmcl.2024.130071

Masataka Michigami , Yuka Kanata , Chang Iou Ven , Ayana Oshima , Asako Yamaguchi-Nomoto , Takayoshi Kinoshita , Takatsugu Hirokawa , Ikuo Fujii

At present, mid-sized binding peptides have emerged as a new class of drug modalities. We have de novo designed a helix–loop–helix (HLH) peptide (MW: ∼4,500), constructed phage-displayed libraries, and screened the libraries against a variety of disease-related proteins to successfully obtain molecular-targeting HLH peptides. The next essential step in developing HLH peptides into therapeutics involves affinity engineering to optimize binding affinity and specificity. Here, we demonstrate deep mutational scanning to improve binding affinity over 1000-fold for an HLH peptide (P8-2KA; K_D = 380 nM) targeting granulocyte colony-stimulation factor receptor (G-CSFR). Site-saturation mutagenesis on the two helices was performed to produce a phage-displayed library that was screened against G-CSFR. The DNA sequences of mutants from the unselected and selected phage libraries were analyzed with next-generation sequencing. The enrichment ratio of each mutant was calculated from the sequencing data to identify beneficial mutations for G-CSFR binding. Grafting of the five beneficial mutations on P8-2KA dramatically increased the binding affinity (K_D = 16 nM), while cyclization of the HLH peptide with an intramolecular disulfide bond further increased binding affinity for G-CSFR (K_D = 0.18 nM). The combined strategy of phage-displayed library selection and deep mutational scanning-guided design generated high-affinity HLH peptides, emphasizing the potential of molecular-targeting HLH peptides as a new drug modality that serves as an alternative to antibodies.

目前，中等大小的结合肽已成为一类新的药物模式。我们从头设计了一个螺旋-环-螺旋（HLH）肽（MW: ~ 4500），构建了噬菌体展示文库，并筛选了针对多种疾病相关蛋白的文库，成功获得了分子靶向的HLH肽。将HLH肽开发为治疗药物的下一个关键步骤涉及亲和工程，以优化结合亲和性和特异性。在这里，我们展示了深度突变扫描，以提高超过1000倍的结合亲和力的HLH肽(P8-2KA；KD = 380 nM)靶向粒细胞集落刺激因子受体（G-CSFR）。在两个螺旋上进行位点饱和诱变，产生一个噬菌体展示文库，该文库对G-CSFR进行了筛选。利用新一代测序技术分析未选择和选择噬菌体文库突变体的DNA序列。根据测序数据计算每个突变体的富集比，以确定G-CSFR结合的有益突变。在P8-2KA上接枝5个有益突变显著提高了G-CSFR的结合亲和力（KD = 16 nM），而用分子内二硫键环化HLH肽进一步提高了G-CSFR的结合亲和力（KD = 0.18 nM）。噬菌体展示文库选择和深度突变扫描引导设计相结合的策略产生了高亲和力的HLH肽，强调了分子靶向HLH肽作为替代抗体的新药物模式的潜力。

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引用次数: 0

Classifying covalent protein binders by their targeted binding site 根据目标结合位点对共价蛋白结合物进行分类。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-10 DOI: 10.1016/j.bmcl.2024.130067

Walaa A. Bedewy , John W. Mulawka , Marc J. Adler

Covalent protein targeting represents a powerful tool for protein characterization, identification, and activity modulation. The safety of covalent therapeutics was questioned for many years due to the possibility of off-target binding and subsequent potential toxicity. Researchers have recently, however, demonstrated many covalent binders as safe, potent, and long-acting therapeutics. Moreover, they have achieved selective targeting among proteins with high structural similarities, overcome mutation-induced resistance, and obtained higher potency compared to non-covalent binders. In this review, we highlight the different classes of binding sites on a target protein that could be addressed by a covalent binder. Upon folding, proteins generate various concavities available for covalent modifications. Selective targeting to a specific site is driven by differences in the geometry and physicochemical properties of the binding pocket residues as well as the geometry and reactivity of the covalent modifier “warhead”. According to the warhead reactivity and the nature of the binding region, covalent binders can alter or lock a targeted protein conformation and inhibit or enhance its activity. We survey these various modification sites using case studies of recently discovered covalent binders, bringing to the fore the versatile application of covalent protein binders with respect to drug discovery approaches.

共价蛋白靶向是蛋白质表征、鉴定和活性调节的有力工具。由于可能脱靶结合和随后的潜在毒性，多年来共价疗法的安全性一直受到质疑。然而，研究人员最近证明了许多共价结合剂是安全、有效和长效的治疗方法。此外，它们在具有高结构相似性的蛋白质之间实现了选择性靶向，克服了突变诱导的抗性，并且与非共价结合物相比获得了更高的效力。在这篇综述中，我们重点介绍了共价结合剂可以解决的靶蛋白上不同类型的结合位点。在折叠时，蛋白质产生各种可用于共价修饰的凹陷。对特定位点的选择性靶向是由结合袋残基的几何和物理化学性质的差异以及共价修饰剂“战斗部”的几何和反应性驱动的。根据战斗部的反应性和结合区的性质，共价结合物可以改变或锁定目标蛋白的构象，抑制或增强其活性。我们使用最近发现的共价结合物的案例研究来调查这些不同的修饰位点，将共价蛋白结合物在药物发现方法方面的通用应用带到前面。

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引用次数: 0

Design and synthesis of N-(3-cyanothiophen-2-yl)-2-phenoxyacetamide-based α-glucosidase inhibitors 基于N-（3-氰噻吩-2-基）-2-苯氧乙酰胺的α-葡萄糖苷酶抑制剂的设计与合成。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-09 DOI: 10.1016/j.bmcl.2024.130068

Yi-Tong Chen , Bo-Wen Wan , Kai-Ming Wang , Kong-Kai Zhu , Ning Meng , Cheng-Shi Jiang , Juan Zhang

This study investigates the design and synthesis of a series of novel selective α-glucosidase inhibitors based on N-(3-cyanothiophen-2-yl)-2-phenoxyacetamide framework, employing a bioisosterism strategy. Among the nineteen newly synthesized analogs, compound 4d9 demonstrated the highest α-glucosidase inhibitory potency (IC₅₀ = 2.11 μM) when compared to the established inhibitors Acarbose (IC₅₀ = 327.0 μM) and HXH8r (IC₅₀ = 15.32 μM), while exhibiting a remarkable 17.48-fold selectivity for α-glucosidase over α-amylase. Kinetic studies revealed that compound 4d9 acts as a non-competitive inhibitor, and its binding interactions were further investigated using molecular docking analysis. Additionally, compound 4d9 showed noncytotoxic effects on human normal hepatocyte (LO2) cells and demonstrated improved metabolic stability in rat plasma. These findings position compound 4d9 as a promising candidate for the development of therapeutics targeting type 2 diabetes.

本研究以N-（3-氰噻吩-2-基）-2-苯氧乙酰胺为骨架，采用生物等构策略，设计和合成了一系列新型选择性α-葡萄糖苷酶抑制剂。19新合成类似物中,化合物4 d9展示了最高α葡糖苷酶抑制能力(IC50 = 2.11 μM)建立抑制剂相比,阿卡波糖(IC50 =  327.0μM)和HXH8r (IC50 =  15.32μM),而表现出显著的选择性为17.48倍α葡糖苷酶在α淀粉酶。动力学研究表明，化合物4d9是一种非竞争性抑制剂，并利用分子对接分析进一步研究了其结合相互作用。此外，化合物4d9对人正常肝细胞（LO2）无细胞毒性作用，并在大鼠血浆中表现出改善的代谢稳定性。这些发现使化合物4d9成为开发针对2型糖尿病的治疗药物的一个有希望的候选者。

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引用次数: 0

Cyclic vinyl sulfones activate NRF2 to protect from oxidative stress-induced programmed necrosis 环乙烯基砜激活NRF2以防止氧化应激诱导的程序性坏死。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-05 DOI: 10.1016/j.bmcl.2024.130058

Pavel Davidovich , Dmitriy Nikolaev , Raniya Khadiullina , Vladislav Gurzhiy , Emil Bulatov

The NRF2 transcriptional factor is a member of cellular stress response machinery and is activated in response to oxidative stress caused either by cellular homeostasis imbalance or by environmental challenges. NRF2 levels are stringently controlled by rapid and continuous proteasomal degradation. KEAP1 is a specific NRF2 binding protein that acts as a bridge between NRF2 and the E3 ligase Cullin-3. In this study, we examine model cyclic vinyl sulfone derivatives as potential NRF2 activating probes. Previously, we and other authors have found anti-inflammatory properties of these compounds in in vivo models; however, the mechanism of action remained unknown. Here, we show that the naphthohydroquinone derivative LCB1353 efficiently stabilizes NRF2 protein levels and upregulates its target genes. At low 5–10 µM concentrations LCB1353 protects non-small cell lung cancer H1299 cells from ferroptotic death induced by cytotoxic concentrations of RSL3, reducing cell death from 90 % to 5 %. Thus, we suggest that cyclic vinyl sulfones are promising scaffolds for the design of protective molecules for conditions associated with toxic and inflammatory levels of oxidative stress.

NRF2转录因子是细胞应激反应机制的一员，在细胞稳态失衡或环境挑战引起的氧化应激反应中被激活。NRF2水平受到快速持续的蛋白酶体降解的严格控制。KEAP1是一种特异性NRF2结合蛋白，作为NRF2和E3连接酶Cullin-3之间的桥梁。在这项研究中，我们研究了模型环乙烯基砜衍生物作为潜在的NRF2激活探针。之前，我们和其他作者已经在体内模型中发现了这些化合物的抗炎特性；然而，其作用机制尚不清楚。本研究表明，萘对苯二酚衍生物LCB1353能有效稳定NRF2蛋白水平并上调其靶基因。在低5-10 µM浓度下，LCB1353保护非小细胞肺癌H1299细胞免受RSL3细胞毒性浓度诱导的铁致死亡，将细胞死亡率从90% %降低到5% %。因此，我们认为环乙烯基砜是设计与氧化应激毒性和炎症水平相关的保护分子的有希望的支架。

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引用次数: 0

Development and characterization of pyridyl carboxamides as potent and highly selective Nav1.8 inhibitors 吡啶基羧酰胺作为高效、高选择性Nav1.8抑制剂的开发与表征。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-05 DOI: 10.1016/j.bmcl.2024.130059

Michael Poslusney , Glen Ernst , Yifang Huang , Aaron C. Gerlach , Mark L. Chapman , Sónia Santos , James C. Barrow

The voltage-gated sodium channel Na_v1.8 (SCN10A) has strong genetic and pharmacological validation as a potential target for treating acute and chronic pain. While several different chemotypes have been advanced as selective inhibitors, a quinoxaline carboxamide core structure was identified as a particularly attractive core structure due to very high sodium channel subtype selectivity. However, poor solubility and overall ADME properties need to be improved. Scaffold hopping to a central trifluoromethyl pyridine followed by optimization of distal substituents resulted in improved overall properties. Several advanced lead compounds have been identified with excellent potency, selectivity, solubility, and pharmacokinetics. Preliminary mechanism of action studies suggest that this class of compounds are voltage and state independent inhibitors that bind to a novel site on the Na_v1.8 channel.

电压门控钠通道Nav1.8 （SCN10A）作为治疗急性和慢性疼痛的潜在靶点具有很强的遗传学和药理学验证。虽然几种不同的化学型已经作为选择性抑制剂被提出，但由于具有非常高的钠通道亚型选择性，喹诺啉羧酰胺核心结构被确定为特别有吸引力的核心结构。然而，ADME的溶解度差和整体性能有待改善。支架跳跃到中心三氟甲基吡啶，然后优化远端取代基，从而改善了整体性能。一些先进的先导化合物已被确定具有良好的效力，选择性，溶解度和药代动力学。初步的作用机制研究表明，这类化合物是电压和状态无关的抑制剂，可结合Nav1.8通道上的新位点。

引用次数: 0

Identification of N-phenyl-N-(quinolin-4-yl) amino carboxylic acids as URAT1 inhibitors with hypouricemic effects 具有降尿酸作用的URAT1抑制剂n-苯基- n-（喹啉-4-基）氨基羧酸的鉴定

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-12-04 DOI: 10.1016/j.bmcl.2024.130053

Xianxin Hou , Mengjie Shao , Lei Zhang , Ying Yang , Zhiyan Xiao

Urate transporter 1 (URAT1) is a therapeutic target for the treatment of hyperuricemia and gout. However, the application of currently marketed URAT1 inhibitors is hampered by insufficient efficacy and poor safety profiles. A series of N-phenyl-N-(quinolin-4-yl) amino carboxylic acids were designed by adopting strategies of molecular hybridization, scaffold hopping, and functional variation. Most compounds showed apparent inhibitory activity against URAT1, and the most active compound 7 exhibited an IC₅₀ of 0.18 μ M, which was comparable to the clinically available drug benzbromarone (IC₅₀ = 0.39 μ M). When tested in parallel with benzbromarone, compound 7 showed significant uric acid-lowering effect in a hyperuricemia zebrafish model induced by potassium oxonate and xanthine sodium salt. Compound 7 was also more metabolically stable than benzbromarone in mouse liver microsomes. The results suggested potential therapeutic benefits of these compounds in the treatment of hyperuricemia and gout.

尿酸转运蛋白1 （URAT1）是治疗高尿酸血症和痛风的治疗靶点。然而，目前上市的URAT1抑制剂的应用受到疗效不足和安全性差的阻碍。采用分子杂交、支架跳跃和功能变异等方法，设计了一系列n-苯基- n-（喹啉-4-基）氨基羧酸。大多数化合物对URAT1具有明显的抑制活性，其中活性最高的化合物7的IC50为0.18 μ M，与临床常用药物苯溴马龙（IC50 = 0.39 μ M）相当。与苯溴马隆平行试验，化合物7在氧酸钾和黄嘌呤钠盐诱导的高尿酸血症斑马鱼模型中显示出显著的降尿酸作用。化合物7在小鼠肝微粒体中的代谢稳定性也高于苯溴马隆。结果表明，这些化合物在治疗高尿酸血症和痛风方面具有潜在的治疗效益。

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引用次数: 0