European Journal of Medicinal Chemistry最新文献_第10页

Discovery of novel hybrid tryptamine-rivastigmine molecules as potent AChE and BChE inhibitors exhibiting multifunctional properties for the management of Alzheimer's disease 发现新型色胺-利巴斯的明混合分子，作为强效 AChE 和 BChE 抑制剂用于阿尔茨海默病的多功能治疗

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2024.117066

Gauri Shankar , Prabhat Kumar , Sanskriti Rai , Aparajita Ghosh , Tanmaykumar Varma , Mushtaq Ahmad Wani , Sunil Kumar , Upesh Mandloi , Gireesh Kumar Singh , Prabha Garg , Onkar Kulkarni , Saripella Srikrishna , Saroj Kumar , Gyan Modi

Contemporary research evidence has corroborated a gradual loss of central cholinergic neurons in Alzheimer's Disease (AD). This progressive deterioration leads to cognitive dysfunction and impaired motor activity, culminating in the brain cell's death in the disease. The approved drugs for AD treatment can only offer relief from symptoms without addressing the underlying pathological hallmarks of the disease. To address the limitations associated with rivastigmine (RIV), a marketed drug for AD, a series of tryptamine derivatives was designed, synthesized, and evaluated in various in-vitro and in-vivo AD models. Enzyme inhibition studies identified compounds 6d and 6e as the lead molecules with potent inhibitors against AChE (6d, IC₅₀: 0.99 ± 0.009 nM and 6e IC₅₀: 7.97 ± 0.016 nM and BChE (6d, IC₅₀: 27.79 ± 0.21 nM and 6e, IC₅₀: 0.79 ± 0.005 nM), compared to the marketed drug Riv (AChE, IC₅₀: 6630 ± 0.76 nM, BChE IC₅₀ = 91 ± 0.40 nM). The molecular docking and dynamics studies corroborated the enzyme inhibition studies. The PAMPA assay strongly suggested the BBB crossing ability of the lead molecules. Further, 6d and 6e demonstrated the capability to counteract oxidative stress and Aβ_1-42 in various in-vitro studies. Compound 6e exhibited remarkable radical scavenging activity in the DPPH assay (IC₅₀: 22.91 ± 1.73 μM) compared to rivastigmine (% radical scavenging activity: 3.71 ± 0.09 at 200 μM). Interestingly, 6d and 6e exhibited promising activity in the AD Drosophila model by protecting eye phenotypes from degeneration induced by Aβ_1-42 toxicity and reduced mitochondrial and cellular oxidative stress in this model. Furthermore, upon oral administration, 6d and 6e could reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice at 0.3 and 0.5 mg/kg compared to rivastigmine at 3 mg/kg and were found to have potent ex-vivo anti-ChEs properties, which are correlated with the observed pro-cognitive effects in the Morris Water Maze, likely mediated through the inhibition of both cholinesterases. The expression of various neuroprotection markers, such as BDNF and TRKB, was significantly overexpressed compared to the disease control group.

当代研究证据证实，阿尔茨海默病（AD）患者的中枢胆碱能神经元会逐渐丧失。这种逐渐退化的过程导致认知功能障碍和运动能力受损，最终导致脑细胞死亡。已获批准的 AD 治疗药物只能缓解症状，却无法解决该疾病的潜在病理特征。为了解决利伐斯的明（RIV）（一种已上市的治疗注意力缺失症的药物）的局限性，我们设计、合成了一系列色胺衍生物，并在各种体外和体内注意力缺失症模型中进行了评估。酶抑制研究确定化合物 6d 和 6e 为先导分子，对 AChE（6d，IC50：0.99 ± 0.009 nM，6e IC50：7.97 ± 0.016 nM）和 BChE（6d，IC50：27.79 ± 0.21 nM 和 6e，IC50：0.79 ± 0.005 nM）的强效抑制剂。分子对接和动力学研究证实了酶抑制研究。PAMPA 试验有力地证明了先导分子穿越 BBB 的能力。此外，在各种体外研究中，6d 和 6e 显示出了对抗氧化应激和 Aβ1-42 的能力。在 DPPH 试验中，化合物 6e 表现出显著的自由基清除活性（IC50：22.91 ± 1.73 μM），而利伐斯的明的自由基清除活性为 3.71 ± 0.09（200 μM）。有趣的是，6d 和 6e 在注意力缺失果蝇模型中表现出了良好的活性，保护眼睛表型不受 Aβ 1-42 毒性诱导的退化影响，并减少该模型中线粒体和细胞的氧化应激。此外，与利巴斯的明（3 毫克/千克）相比，口服 0.3 和 0.5 毫克/千克的 6d 和 6e 可改善小鼠的空间记忆和认知记忆，从而逆转东莨菪碱诱导的健忘症。与疾病对照组相比，BDNF 和 TRKB 等多种神经保护标志物的表达明显过表达。

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引用次数: 0

Structure-activity relationship study of novel evodiamine amino acid conjugates with potent anti-colorectal cancer efficacy 抗结直肠癌的新型戊二胺氨基酸偶联物构效关系研究

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2024.117132

Shuting Chen , Xi Zhang , Hanxuan Mo , Ying Peng , Zhigang An , Junbo Wu , Xiuzhen Wei , Siyi Zhang , Yongxia Xiong , Weifan Jiang , Xue Peng , Linsheng Zhuo , Zhengwen Lei , Zhen Wang , Zecheng Hu

Evodiamine has been a promising lead structure with broad-spectrum antitumor activity. Druggability optimization is the most challenging part of evodiamine-based lead-to-candidate campaign. Amino acids as building blocks for conjugates are widely incorporated into approved drug and drug candidates, demonstrating highly attractive druggability. Herein, a series of evodiamine amino acid conjugates were designed and synthesized based on the evodiamine lead compound (±)-8b discovered in our previous work. The structure−activity relationship (SAR) studies culminated in the identification of a promising conjugate (−)-15h featuring a N-Boc-l-glutamine group and a chiral carbon atom (sinister), which exhibited nanomolar antiproliferative activity against LoVo and RKO colorectal cancer cells. Moreover, (−)-15h could inhibit topoisomerases I, arrest the cell cycle in the G2/M phase, and induce apoptosis. Importantly, (−)-15h (tumor growth inhibition rate was 82.53 % in 40 mpk) showed better efficacy and tolerability to that of parent compound (−)-8b (tumor growth inhibition rate was 51.22 % in 40 mpk) in LoVo xenograft model. Further, (−)-15h (tumor growth inhibition rate was 70.09 % in 40 mpk) showed comparable efficacy and better tolerability to that of topotecan (tumor growth inhibition rate was 70.67 % in 0.5 mpk) in HT-29 xenograft model. Collectively, this study further provided a strong scientific basis for amino acid-based structural modifications and a drug lead for anti-colorectal cancer applications.

evolodiamine是一种具有广谱抗肿瘤活性的先导结构。在以evoldiamine为基础的lead- the -candidate竞选中，drug - ability优化是最具挑战性的部分。氨基酸作为缀合物的构建块被广泛地结合到已批准的药物和候选药物中，显示出高度吸引人的药物性。本文以前期发现的evoldiine先导化合物（±）-8b为基础，设计并合成了一系列evoldiine氨基酸偶联物。结构-活性关系（SAR）研究最终确定了一个具有n - boc - l -谷氨酰胺基团和一个手性碳原子（sinister）的有前途的共轭物(−)-15h，该共轭物对LoVo和RKO结直肠癌细胞具有纳米摩尔抗增殖活性。此外，(−)-15h可以抑制拓扑异构酶I，使细胞周期停留在G2/M期，诱导细胞凋亡。重要的是，在LoVo异种移植物模型中，(−)-15h （40 mpk下肿瘤生长抑制率为82.53%）比母体化合物(−)-8b （40 mpk下肿瘤生长抑制率为51.22%）表现出更好的疗效和耐受性。此外，在HT-29异种移植物模型中，(−)-15h （40 mpk时肿瘤生长抑制率为70.09%）与拓扑替康（0.5 mpk时肿瘤生长抑制率为70.67%）的疗效相当，耐受性更好。总之，本研究进一步为基于氨基酸的结构修饰和抗结直肠癌药物的应用提供了强有力的科学依据。

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引用次数: 0

Efficacy and molecular mechanisms of hesperidin in mitigating Alzheimer's disease: A systematic review 橙皮苷减轻阿尔茨海默病的疗效和分子机制：系统综述

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2024.117144

Xu Han , Yuting Zhang , Lijuan Zhang , Yanyan Zhuang , Yu Wang

Hesperidin, a flavonoid glycoside, is a natural phenolic compound that has broad biological effects. Increasing evidence suggests that hesperidin inhibits the occurrence and development of neurodegenerative diseases, including Alzheimer's disease (AD). This article reviews the neuropharmacological mechanisms of hesperidin in the prevention and treatment of AD through in vitro and in vivo studies. A systematic review of preclinical studies was conducted using PubMed, Web of Science, Scopus, and Google Scholar (up to July 1, 2024). The neuroprotective potential of hesperidin was mediated through mechanisms such as inhibition of β-amyloid (Aβ) aggregation, enhancement of endogenous antioxidant defense functions, reduction of neuroinflammation and apoptosis, improvement of mitochondrial dysfunction, regulation of autophagy, and promotion of neurogenesis. Despite various preclinical studies on the role of hesperidin in AD, its exact effects on humans remain unclear. Few clinical trials have indicated that dietary supplements rich in hesperidin can improve cerebral blood flow, cognition, and memory performance. The neuroprotective effect of hesperidin may be exerted via regulating different molecular pathways, including the RAGE/NF-κB, Akt/Nrf2, and AMPK/BDNF/CREB pathways. However, further clinical trials are needed to confirm the neuroprotective effects of this natural flavonoid compound and to assess its safety.

橙皮苷是一种具有广泛生物学效应的天然酚类化合物。越来越多的证据表明橙皮苷抑制神经退行性疾病的发生和发展，包括阿尔茨海默病（AD）。本文通过体外和体内研究综述橙皮苷预防和治疗AD的神经药理学机制。通过PubMed、Web of Science、Scopus和谷歌Scholar（截止到2024年7月1日）对临床前研究进行了系统回顾。橙皮苷的神经保护作用可能通过抑制β-淀粉样蛋白（Aβ）聚集、增强内源性抗氧化防御功能、减少神经炎症和凋亡、改善线粒体功能障碍、调节自噬和促进神经发生等机制介导。尽管对橙皮苷在阿尔茨海默病中的作用进行了各种临床前研究，但其对人类的确切影响仍不清楚。很少有临床试验表明富含橙皮苷的膳食补充剂可以改善脑血流量，认知和记忆性能。橙皮苷的神经保护作用可能通过调节RAGE/NF-κB、Akt/Nrf2、AMPK/BDNF/CREB等不同的分子通路来发挥。然而，需要进一步的临床试验来证实这种天然类黄酮化合物的神经保护作用并评估其安全性。

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引用次数: 0

Prodrugging fungicidal amphotericin B significantly decreases its toxic effects 前药杀菌两性霉素B显著降低其毒性作用

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2024.117157

Ondřej Štěpánek , Marie Parigger , Eliška Procházková , Adéla Čmoková , Miroslav Kolařík , Helena Dračínská , Věra Černá , Květa Kalíková , Valéria Grobárová , Jan Černý , Jakob Scheler , Gottfried Schweiger , Ulrike Binder , Ondřej Baszczyňski

Amphotericin B (AmB) is one of the most effective antifungal drugs, with a strong, dose-dependent activity against most Candida and Aspergillus species responsible for life-threatening infections. However, AmB is severely toxic, which hinders its broad use. In this proof-of-concept study, we demonstrate that prodrugging AmB considerably decreases AmB toxicity without affecting its fungicidal activity. For this purpose, we modified the AmB structure by attaching a designer phosphate promoiety, thereby switching off its mode of action and preventing its toxic effects. The original fungicidal activity of AmB was then restored upon prodrug activation by host plasma enzymes. These AmB prodrugs showed a safer toxicity profile than commercial AmB deoxycholate in Candida and Aspergillus species and significantly prolonged larval survival of infected Galleria mellonella larvae. Based on these findings, prodrugging toxic antifungals may be a viable strategy for broadening the antifungal arsenal, opening up opportunities for targeted prodrug design.

两性霉素B （AmB）是最有效的抗真菌药物之一，对大多数念珠菌和曲霉菌具有很强的剂量依赖性活性，可导致危及生命的感染。然而，AmB是剧毒的，这阻碍了它的广泛使用。在这个概念验证研究中，我们证明了预用药可以显著降低AmB的毒性，而不影响其杀真菌活性。为此，我们通过附加一个设计磷酸盐启动子来修饰AmB结构，从而关闭其作用模式并防止其毒性作用。AmB在药物前被宿主血浆酶激活后恢复了原有的杀真菌活性。这些AmB前药在假丝酵母菌和曲霉菌中显示出比商业AmB脱氧胆酸盐更安全的毒性，并显著延长了受感染的mellonella幼虫的存活时间。基于这些发现，对毒性抗真菌药物进行前药治疗可能是扩大抗真菌药物库的可行策略，为靶向前药设计开辟了机会。

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引用次数: 0

Inorganic nanoparticles and blood-brain barrier modulation: Advancing targeted neurological therapies

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2025.117357

Zahra Sadat Razavi , Fateme Sadat Razavi , Seyed Sina Alizadeh

The blood-brain barrier (BBB) is a protective barrier that complicates the treatment of neurological disorders. Pharmaceutical compounds encounter significant challenges in crossing the central nervous system (CNS). Nanoparticles (NPs) are promising candidates for treating neurological conditions as they help facilitate drug delivery. This review explores the diverse characteristics and mechanisms of inorganic NPs (INPs), including metal-based, ferric-oxide, and carbon-based nanoparticles, which facilitate their passage through the BBB. Emphasis is placed on the physicochemical properties of NPs such as size, shape, surface charge, and surface modifications and their role in enhancing drug delivery efficacy, reducing immune clearance, and improving BBB permeability. Specific synthesis approaches are demonstrated, with an emphasis on the influence of each one on NP property, biological activity and the capability of an NP for its intended application. As for the advances in the field, the review emphasizes those characterized the NP formulation and surface chemistry that conquered the BBB and tested the need for its alteration. Current findings indicate that NP therapy can in the future enable effective targeting of specific brain disorders and eventually evolve this drug delivery system, which would allow for lower doses with less side effects.

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引用次数: 0

Novel steroidal β-carboline derivatives as promising antibacterial candidates against methicillin-resistant Staphylococcus aureus 抗甲氧西林金黄色葡萄球菌的新型甾体β-碳碱衍生物

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2024.117187

Haibo Huo , Wenjia Dan , Libo Qin , Jiaxue Bo , Xiaonan Zhang , Chaofu Yang , Bianxia Bai , Jiahong Ren , Baojun Shi , Jian Li

A novel series of steroidal β-carboline quaternary ammonium derivatives (SCQADs) derived from natural cholic acid and its derivatives was designed, synthesized and biologically evaluated against four Gram-positive bacteria for the first time. Most of these derivatives exhibited promising antibacterial activity against the tested strains, particularly, compound 21g displayed strong antibacterial activity against MRSA (MIC = 0.5–1 μg/mL) with low cytotoxicity. Meanwhile, derivative 21g was able to quickly kill Gram-positive bacteria within 0.5 h without inducing bacterial resistance. Preliminary mechanistic explorations indicated that compound 21g destroyed bacterial cell membranes to exert its antibacterial effects. Moreover, 21g exhibited high in vivo efficacy and high survival protection in a mouse skin abscess model. These findings suggested that compound 21g has great potential to develop as an antibacterial agent.

以天然胆酸及其衍生物为原料，设计合成了一系列甾体β-碳碱季铵盐衍生物（SCQADs），并首次进行了抗4种革兰氏阳性菌的生物学评价。其中化合物21g对MRSA具有较强的抗菌活性（MIC = 0.5 ~ 1 μg/mL），且具有较低的细胞毒性。同时，衍生物21g能在0.5 h内快速杀死革兰氏阳性菌，且不产生细菌耐药性。初步机理探索表明化合物21g破坏细菌细胞膜发挥抑菌作用。此外，21g在小鼠皮肤脓肿模型中具有较高的体内疗效和较高的存活保护作用。这些结果表明，化合物21g作为一种抗菌剂具有很大的开发潜力。

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引用次数: 0

Synthetic approaches and clinical applications of representative HDAC inhibitors for cancer therapy: A review 肿瘤治疗中典型HDAC抑制剂的合成方法及临床应用综述

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2024.117185

Zhengming Lv , Tianyi Ji , Jie Liu, Xu Sun, Huimin Liang

Histone deacetylase (HDAC) inhibitors are a promising class of epigenetic modulators in cancer therapy. This review provides a comprehensive analysis of recent synthetic strategies and clinical applications of key HDAC inhibitors for oncology. HDACs play a critical role in modulating chromatin structure and gene expression by removing acetyl groups from histone proteins, leading to transcriptional repression of tumor suppressor genes. By inhibiting HDAC activity, HDAC inhibitors restore normal acetylation patterns, reactivating silenced tumor suppressor genes and inducing cell cycle arrest, apoptosis, and autophagy in cancer cells. The review explores synthetic approaches to developing representative HDAC inhibitors that have been approved or in various clinical trials. Through an integrated perspective on the synthesis, mechanism of action, and clinical advancements of HDAC inhibitors, this review aims to guide future research toward next-generation HDAC inhibitors that could enhance cancer treatment efficacy while minimizing toxicity, offering insights for chemists and clinicians in the field of oncology.

组蛋白去乙酰化酶（HDAC）抑制剂是一类在癌症治疗中很有前途的表观遗传调节剂。本文综述了近年来肿瘤HDAC抑制剂的合成策略和临床应用的综合分析。hdac在调节染色质结构和基因表达中发挥关键作用，通过去除组蛋白中的乙酰基，导致肿瘤抑制基因的转录抑制。通过抑制HDAC活性，HDAC抑制剂恢复正常的乙酰化模式，重新激活沉默的肿瘤抑制基因，诱导癌细胞的细胞周期阻滞、细胞凋亡和自噬。该综述探讨了开发已批准或在各种临床试验中具有代表性的HDAC抑制剂的合成方法。本文将从HDAC抑制剂的合成、作用机制和临床进展等方面进行综述，旨在指导未来对下一代HDAC抑制剂的研究，以提高癌症治疗效果，同时降低毒性，为肿瘤学领域的化学家和临床医生提供见解。

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引用次数: 0

Corrigendum to “Antibacterial and antifungal pyrazoles based on different construction strategies” [Euro. J. Med. Chem. 282 (2025) 117081] 基于不同构建策略的抗菌和抗真菌吡唑"[欧洲医学化学杂志 282 (2025) 117081] 更正

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2024.117147

Muneeb Ur Rehman , Fang He , Xi Shu, Ju Guo, Ziwei Liu, Shuang Cao, Sihui Long

引用次数: 0

Impact of natural compounds on peroxisome proliferator-activated receptor: Molecular effects and its importance as a novel therapeutic target for neurological disorders 天然化合物对过氧化物酶体增殖物激活受体的影响：分子效应及其作为神经疾病新治疗靶点的重要性

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2024.117170

Zhe Zhu , Yadi Guan , Songlan Gao , Feng Guo , Dong Liu , Honglei Zhang

Neurological disorders refer to the pathological changes of the nervous system involving multiple pathological mechanisms characterized by complex pathogenesis and poor prognosis. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor that is a member of the nuclear receptor superfamily. PPAR has attracted considerable attention in the past decades as one of the potential targets for the treatment of neurological disorders. Several in vivo and in vitro studies have confirmed that PPARs play a neuroprotective role by regulating multiple pathological mechanisms. Several selective PPAR ligands, such as thiazolidinediones and fibrates, have been approved as pharmacological agonists. Nevertheless, PPAR agonists cause a variety of adverse effects. Some natural PPAR agonists, including wogonin, bergenin, jujuboside A, asperosaponin VI, monascin, and magnolol, have been introduced as safe agonists, as evidenced by clinical or preclinical experiments. This review summarizes the effects of phytochemicals on PPAR receptors in treating various neurological disorders. Further, it summarizes recent advances in phytochemicals as potential, safe, and promising PPAR agonists to provide insights into understanding the PPAR-dependent and independent cascades mediated by phytochemicals. The phytochemicals exhibited potential for treating neurological disorders by inhibiting neuroinflammation, exerting anti-oxidative stress and anti-apoptotic activities, promoting autophagy, preventing demyelination, and reducing brain edema and neurotoxicity. This review presents data that will help clarify the potential mechanisms by which phytochemicals act as pharmacological agonists of PPARs in the treatment of neurological disorders. It also provides insights into developing new drugs, highlighting phytochemicals as potential, safe, and promising PPAR agonists. Additionally, this review aims to enhance understanding of both PPAR-dependent and independent pathways mediated by phytochemicals.

神经系统疾病是指涉及多种病理机制的神经系统病变，其发病机制复杂，预后差。过氧化物酶体增殖体激活受体（PPAR）是一种配体激活的转录因子，是核受体超家族的成员。在过去的几十年里，PPAR作为治疗神经系统疾病的潜在靶点之一引起了相当大的关注。多项体内和体外研究证实，ppar通过调节多种病理机制发挥神经保护作用。一些选择性PPAR配体，如噻唑烷二酮类和贝特类，已被批准作为药物激动剂。然而，PPAR激动剂引起各种不良反应。一些天然的PPAR激动剂，包括枸杞素、山药根素、红枣苷A、木皂苷VI、红霉素和厚朴酚，已被作为安全的激动剂引入临床或临床前实验。本文就植物化学物质对PPAR受体的作用在治疗各种神经系统疾病中的作用进行综述。此外，它总结了植物化学物质作为潜在的、安全的和有前途的PPAR激动剂的最新进展，以提供对植物化学物质介导的PPAR依赖和独立级联反应的理解。这些植物化学物质通过抑制神经炎症、发挥抗氧化应激和抗凋亡活性、促进自噬、防止脱髓鞘、减少脑水肿和神经毒性，显示出治疗神经系统疾病的潜力。本综述提供的数据将有助于阐明植物化学物质作为ppar药物激动剂治疗神经系统疾病的潜在机制。它还为开发新药提供了见解，突出了植物化学物质作为潜在的、安全的和有前途的PPAR激动剂。此外，本综述旨在加强对植物化学物质介导的ppar依赖和独立途径的理解。

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引用次数: 0

Development of dual V1a/V2 antagonists containing triazolobenzazepine scaffold 开发含有三唑并氮杂卓支架的 V1a/V2 双拮抗剂

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-02-05 DOI: 10.1016/j.ejmech.2024.117069

Gábor Varró, Éva Bozó, Krisztina Vukics, Ferenc Baska, Gábor Szántó, Balázs Krámos, Katalin Domány-Kovács, Krisztina Szondiné Kordás, Mónika Vastag, Ildikó Magdó, Imre Bata

The development of a dual V1a/V2 antagonist compound is a complex and challenging task. Conivaptan is up to now the only known V1a/V2 antagonist which was approved for the treatment of euvolemic hyponatremia. Previously, we reported RGH-122, a novel selective V1a antagonist compound. Herein, we describe several promising dual antagonist compounds, which are derived from RGH-122 by using modifications in its tail region. These modifications can result in excellent binding affinity on both V1a and V2 receptors.

开发 V1a/V2 双拮抗剂化合物是一项复杂而具有挑战性的任务。康尼伐他坦（Conivaptan）是迄今为止已知的唯一一种V1a/V2拮抗剂，已被批准用于治疗无水低钠血症。此前，我们曾报道过一种新型选择性 V1a 拮抗剂化合物 RGH-122。在此，我们介绍了几种很有前景的双拮抗剂化合物，它们是通过对 RGH-122 的尾部区域进行修饰而衍生出来的。这些修饰可使其在 V1a 和 V2 受体上产生极佳的结合亲和力。

引用次数: 0