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

N-[3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl]-heteroaromatic carboxamide as selective α1A/1D-adrenoceptor antagonists: SAR study and metabolic stability evaluation N-[3-（4-（2-甲氧基苯基）哌嗪-1-基）丙基]-杂芳香carboxamide作为选择性α1A/ 1d肾上腺素受体拮抗剂：SAR研究和代谢稳定性评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-13 DOI: 10.1016/j.bmcl.2025.130507

Ruxia Duan , Linxin Zhou , Ran Chen , Yajian Huang , Dan Wu , Tomohiko Ohwada , Wei Yi , Junjun Huang

Dual α_1A/1D-adrenergic receptor (AR) antagonists are a mainstay treatment for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Building on the phenylpiperazine pharmacophore of naftopidil, our previous work identified the linker region as a critical structural determinant for subtype selectivity. However, we recognized that the secondary hydroxyl group within the previously employed linker (e.g., in lead R-17) could represent a potential metabolic liability. In this study, we strategically optimized the linker moiety to achieve a precise balance between subtype selectivity and metabolic stability. We designed and synthesized nineteen novel propane-linked derivatives by eliminating the hydroxyl group and introducing diverse aromatic carboxamide moieties. Among them, compound 15 featuring a 5-benzo[d][1,3]dioxole group emerged as a highly potent α_1A/1D antagonist. Structure-activity relationship (SAR) and molecular docking confirmed that the streamlined propane linker retains the optimal chain length to prevent the key salt bridge interaction with D^3.32 in the α_1B subtype, thereby preserving the structural basis for high selectivity. Crucially, our head-to-head evaluation in rat liver microsomes validated our design hypothesis: the removal of the hydroxyl group dramatically improved metabolic stability, extending the half-life (T_1/2) from 6.1 min (R-17) to 31.5 min (15). This work establishes compound 15 as a promising lead candidate that successfully integrates the selectivity-determining linker scaffold with enhanced drug-like properties.

双α1A/ 1d肾上腺素能受体（AR）拮抗剂是治疗与良性前列腺增生（BPH）相关的下尿路症状（LUTS）的主要药物。基于萘托地尔的苯哌嗪药效团，我们之前的工作确定了连接区域是亚型选择性的关键结构决定因素。然而，我们认识到先前使用的连接物（例如铅R-17）中的二级羟基可能代表潜在的代谢倾向。在这项研究中，我们战略性地优化了连接子片段，以实现亚型选择性和代谢稳定性之间的精确平衡。我们通过消去羟基和引入多种芳族羧胺基团，设计合成了19种新型丙烷链衍生物。其中含有5-苯并[d][1,3]二恶唑基团的化合物15是一种高效的α1A/1D拮抗剂。结构-活性关系（SAR）和分子对接证实，流线型丙烷连接剂保留了最佳链长，以防止α1B亚型中D3.32与关键盐桥相互作用，从而保留了高选择性的结构基础。至关重要的是，我们在大鼠肝微粒体中进行的头对头评估验证了我们的设计假设：去除羟基显著改善了代谢稳定性，将半衰期（T1/2）从6.1 min （R-17）延长到31.5 min（15）。这项工作建立了化合物15作为一个有希望的先导候选物，它成功地整合了决定选择性的连接支架和增强的药物样性质。

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引用次数: 0

Therapeutic potential of STK17A targeted therapies STK17A靶向治疗的治疗潜力。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-12 DOI: 10.1016/j.bmcl.2025.130506

Hafsa Ouaakki , Eduardo Bravo Jr , Justin Taylor , Yangbo Feng

STK17A (serine/threonine kinase 17a), also known as DRAK1 (death-associated protein kinase-related apoptosis-inducing protein kinase 1), is a member of the death-associated protein kinase (DAPK) family and acts as a positive regulator of apoptosis. STK17A is a dark kinase and is an understudied member in the DAPK family. Thus far, it has been found to serve a significant role in cell proliferation, apoptosis, tumor metastasis, and tumorigenesis. This review summarizes the structure of STK17A, its reported biological functions, and expression in cancer. Small molecule inhibitors for STK17A, including those specifically developed for STK17A and those designed for other kinases but also inhibit STK17A as an unintended target, are discussed. Finally, some outlooks for drug discovery regarding STK17A are described.

STK17A（丝氨酸/苏氨酸激酶17a），也被称为DRAK1（死亡相关蛋白激酶相关凋亡诱导蛋白激酶1），是死亡相关蛋白激酶（DAPK）家族的成员，是细胞凋亡的积极调节因子。STK17A是一种暗激酶，是DAPK家族中一个未被充分研究的成员。目前已发现它在细胞增殖、细胞凋亡、肿瘤转移和肿瘤发生中起重要作用。本文就STK17A的结构、已报道的生物学功能及其在肿瘤中的表达进行综述。讨论了STK17A的小分子抑制剂，包括专门为STK17A开发的抑制剂和为其他激酶设计的抑制剂，但也将STK17A作为非预期靶点抑制。最后，对STK17A的药物开发前景进行了展望。

引用次数: 0

Design, synthesis, and antibacterial activity evaluation of tryptanthrin derivatives 色氨酸衍生物的设计、合成及抗菌活性评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-11 DOI: 10.1016/j.bmcl.2025.130503

Bing-Yuan Yan , Ran-Qi Feng , Chen Qu , Xu-Wen Li

A series of tryptanthrin derivatives were designed, synthesized and evaluated for their antibacterial activity against the marine pathogen Vibrio parahaemolyticus. The bioactivity assessment revealed that compounds 7h and 8c exhibited potent antibacterial effects against V. parahaemolyticus without cytotoxicity toward mammalian cells. Structure-activity relationship (SAR) analysis indicated that electron-withdrawing substituents on the phenyl ring played a crucial role in enhancing antibacterial activity. Furthermore, compounds 7h and 8c demonstrated strong antibiofilm activity at concentrations of 8 μg/mL and 6 μg/mL, respectively, effectively inhibiting both biofilm formation and maturation in V. parahaemolyticus. These results demonstrate that compounds 7h and 8c exhibited efficacy against drug-resistant Vibrio strains, providing insight into the application of tryptanthrin derivatives as potential antibacterial agents.

设计、合成了一系列色氨酸衍生物，并对其对海洋致病菌副溶血性弧菌的抑菌活性进行了评价。生物活性评价表明，化合物7h和8c对副溶血性弧菌具有较强的抗菌作用，对哺乳动物细胞无细胞毒性。构效关系分析表明，苯基环上的吸电子取代基对提高抗菌活性起着至关重要的作用。此外，化合物7h和8c在浓度分别为8 μg/mL和6 μg/mL时表现出较强的抗生物膜活性，可有效抑制副溶血性弧菌生物膜的形成和成熟。这些结果表明，化合物7h和8c对耐药弧菌具有抑制作用，为色氨酸衍生物作为潜在抗菌剂的应用提供了新的思路。

引用次数: 0

Design, synthesis and biological evaluation of ALK/HDAC dual-targeting agents ALK/HDAC双靶向药物的设计、合成及生物学评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-11 DOI: 10.1016/j.bmcl.2025.130495

Ye Kong , Shunda Li , Xintong Xue , Huiping Liu , Ruiwei Fu , Yan Gao , Yingjie Zhang , Xia Xue

Dual inhibition of ALK and HDACs might be an effective cancer treatment approach. We designed and synthesized novel dual ALK and HDAC inhibitors using molecular hybridization and pharmacophore merging. In enzymatic assays, compound 19b showed dual inhibitory activity against ALK (ALK WT IC₅₀ = 8.0 ± 1.2 nM) and HDACs (HeLa cell nuclear extract IC₅₀ = 1.18 ± 0.22 μM). Notably, 19b exhibited ~5-fold greater inhibition than Staurosporine and approved ALK inhibitor Brigatinib against the ALK G1202R mutant. Additionally, 19b demonstrated strong activity in ALK-related neuroblastoma SK-N-BE2 cells, comparable to controls SAHA, MS275, and Brigatinib. In SK-N-BE2 cells, 19b treatment led to increased apoptosis and G2/M arrest. Docking studies explained the potent dual inhibition by 19b. These findings support the promise of 19b as a dual ALK/HDAC inhibitor for managing neuroblastoma, especially ALK-positive cancer.

双重抑制ALK和hdac可能是一种有效的癌症治疗方法。我们利用分子杂交和药效团合并的方法设计合成了新的ALK和HDAC双抑制剂。在酶化验,对碱性化合物19 b显示双重抑制活动(alaska airlines WT IC50 = 8.0 ±1.2  海里),hdac(海拉细胞核提取IC50 = 1.18 ±0.22  μM)。值得注意的是，19b对ALK G1202R突变体的抑制作用比Staurosporine和批准的ALK抑制剂Brigatinib强5倍。此外，19b在alk相关神经母细胞瘤SK-N-BE2细胞中表现出很强的活性，与对照SAHA、MS275和Brigatinib相当。在SK-N-BE2细胞中，19b处理导致凋亡增加和G2/M阻滞。对接研究解释了19b的双重抑制作用。这些发现支持19b作为ALK/HDAC双重抑制剂治疗神经母细胞瘤，特别是ALK阳性癌症的前景。

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引用次数: 0

Design, synthesis and biological evaluation of coumarin-based HDAC6 inhibitors for the treatment of ulcerative colitis 以香豆素为基础的HDAC6抑制剂治疗溃疡性结肠炎的设计、合成和生物学评价

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-10 DOI: 10.1016/j.bmcl.2025.130500

Xiang Qiu , Lingling Dong , Hongzhen Shu , Guangxing Yu , Yuling Tong , Hengfan Ni , Shunjie Zhang

Novel selective histone deacetylase 6 (HDAC6) inhibitors using coumarin moiety as the cap were designed, synthesized and evaluated for HDAC enzymatic assays and anti-inflammatory tests. Among them, compound 24 emerged as the most promising candidate, demonstrating potent HDAC6 inhibition with an IC₅₀ value of 17 nM and exhibiting 32.39-fold selectivity over HDAC1. In vitro studies revealed that compound 24 efficiently suppressed nitric oxide production in RAW264.7 mouse macrophages, with an IC₅₀ value of 2.31 μM. Furthermore, human liver microsome tests confirmed its excellent metabolic stability, with a half-life of 59.74 min. Following administration at 30 mg/kg, compound 24 effectively maintain the integrity of colon tissue of DSS-induced ulcerative colitis mice model. Notably, its therapeutic efficacy was comparable to that of tofacitinib. These findings suggested that compound 24 was a promising anti-inflammatory candidate for selective HDAC6 inhibitor and deserves further investigation.

设计、合成了以香豆素片段为帽的新型选择性组蛋白去乙酰化酶6 （HDAC6）抑制剂，并对其进行了HDAC酶促试验和抗炎试验评价。其中，化合物24是最有希望的候选物，其抑制HDAC6的IC50值为17 nM，对HDAC1的选择性为32.39倍。体外研究表明，化合物24能有效抑制RAW264.7小鼠巨噬细胞产生一氧化氮，IC50值为2.31 μM。此外，人肝微粒体试验证实其具有良好的代谢稳定性，半衰期为59.74 min。30 mg/kg给药后，化合物24能有效维持dss致溃疡性结肠炎小鼠模型结肠组织的完整性。值得注意的是，其治疗效果与托法替尼相当。这些结果表明，化合物24是一种有前景的抗炎候选药物，值得进一步研究。

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引用次数: 0

Bicyclic peptide-based CPPTACs for extracellular and cell membrane protein degradation 基于双环肽的胞外和细胞膜蛋白降解cpptac。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-08 DOI: 10.1016/j.bmcl.2025.130496

Jinyu Bai , Huaihuai Shi , Jitun Chen , Hui Tian , Jiaxin Liang , Bichun Chen , Jiazhong Li , Lijing Fang

Extracellular and cell membrane proteins are critical for maintaining physiological homeostasis and the abnormal expression of these proteins cause various diseases. Consequently, the development of targeted degradation strategy for these proteins represents a significant therapeutic opportunity. Leveraging cell-penetrating peptide (CPP)-induced endocytosis and lysosomal delivery, bicyclic CPP-mediated lysosome-targeting chimeras (CPPTACs) were developed to selectively degrade extracellular and cell surface proteins. Constructed by the conjugation of a bicyclic CPP containing the KRK motif with different target protein-binding molecules, these bicyclic peptide-based CPPTACs demonstrate the ability to enhance cellular uptake and facilitate the rapid degradation of protein targets via the endo-lysosomal pathway. These findings support the advancement of bicyclic peptide-based CPPTACs in pharmaceutical drug discovery.

细胞外蛋白和细胞膜蛋白对维持生理稳态至关重要，这些蛋白的异常表达可引起各种疾病。因此，这些蛋白质的靶向降解策略的发展代表了一个重要的治疗机会。利用细胞穿透肽（CPP）诱导的内吞作用和溶酶体递送，开发了双环CPP介导的溶酶体靶向嵌合体（cpptac），以选择性地降解细胞外和细胞表面蛋白。这些基于双环肽的cpptac是由含有KRK基元的双环CPP与不同的靶蛋白结合分子偶联而成，具有增强细胞摄取和通过内溶酶体途径促进靶蛋白快速降解的能力。这些发现支持了双环肽基cpptac在药物发现中的进展。

引用次数: 0

Identification of flavonoid-based small molecule inhibitors with dual-targeting capability against RdRp and Mpro of SARS-CoV-2 双靶向SARS-CoV-2病毒RdRp和Mpro的类黄酮小分子抑制剂的鉴定

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-08 DOI: 10.1016/j.bmcl.2025.130501

Yanlei Su , Yujia Wang , Jianyuan Zhao , Keyu Guo , Xuhong Duan , Honghai Wu , Dianxing Sun , Jing Zhang , Shan Cen

Due to issues of high transmissibility, immune evasion, and drug resistance in SARS-CoV-2 variants, there is an urgent need for novel antiviral drugs. Plant-derived flavonoids such as baicalein (EC₅₀ = 4.5 μM) and baicalin (EC₅₀ = 9.0 μM) exhibit broad-spectrum antiviral potential via RNA-dependent RNA polymerase (RdRp) inhibition. Based on this, our study identified two derivatives through pharmacophore alignment between flavonoid scaffolds and the main protease (Mpro) inhibitor 13b: a psoralen-derived lignan (Comp.1) and a novel isoflavone analog (Comp.2), with dual-targeting capability against SARS-CoV-2 RdRp and Mpro. Computational docking elucidated the binding interactions of compounds with RdRp, Mpro, and the L50F/E166V double mutant Mpro. In vitro assays demonstrated that Comp.1 exhibited micromolar-range inhibitory effects on both RdRp (EC₅₀: 25.45 μM) and Mpro (IC₅₀: 125.4 μM), outperforming Comp.2. Both compounds maintained inhibitory activity against the PF07321332-resistant L50F/E166V double mutant Mpro, with IC₅₀ fold-change values of 1.23 and 1.18, respectively, compared to an 8.62-fold reduction for PF07321332. However, ADMET evaluation indicated that although compounds met basic physicochemical criteria (including molecular weight, TPSA, and compliance with Lipinski's Rule of Five), they still presented critical toxicological liabilities, including high genotoxicity risk (Comp.1: 0.838 probability) and CYP3A4 inhibition (>0.97), necessitating extensive structural optimization. This study confirms that flavonoid derivatives represent promising starting points for developing resistance-aware antiviral agents, though their current profiles classify them as early-stage leads requiring substantial optimization.

由于SARS-CoV-2变体存在高传播性、免疫逃逸和耐药等问题，迫切需要新型抗病毒药物。黄芩素（EC₅₀ = 4.5 μM）和黄芩苷（EC₅₀ = 9.0 μM）等植物衍生的黄酮类化合物通过RNA依赖性RNA聚合酶（RdRp）抑制表现出广谱抗病毒潜力。基于此，本研究通过黄酮类化合物支架与主要蛋白酶（Mpro）抑制剂13b之间的药效团比对，鉴定出两种衍生物：补骨脂素衍生木脂素（comp1）和新型异黄酮类似物（comp2），它们具有针对SARS-CoV-2 RdRp和Mpro的双重靶向能力。计算对接阐明了化合物与RdRp、Mpro和L50F/E166V双突变体Mpro的结合相互作用。体外实验表明，Comp.1对RdRp （EC₅₀：25.45 μM）和Mpro （IC₅₀：125.4 μM）都具有微摩尔范围的抑制作用，优于Comp.2。这两种化合物对PF07321332抗性L50F/E166V双突变体Mpro都保持抑制活性，IC₅₀折叠变化值分别为1.23和1.18，而PF07321332的折叠变化值为8.62倍。然而，ADMET评估表明，虽然化合物符合基本的理化标准（包括分子量、TPSA和Lipinski's Rule of Five），但它们仍然存在严重的毒理学缺陷，包括高遗传毒性风险（p.1: 0.838概率）和CYP3A4抑制（>0.97），需要进行广泛的结构优化。这项研究证实，类黄酮衍生物代表了开发耐药性感知抗病毒药物的有希望的起点，尽管它们目前的概况将它们归类为需要大量优化的早期先导物。

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引用次数: 0

A self-assembling peptide platform enables plasma membrane protein degradation 自组装肽平台使质膜蛋白降解。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-08 DOI: 10.1016/j.bmcl.2025.130504

Wenjie Zhou , Yanyan Li , Wenli Shi , Binghua Cheng , Jiaming Liang , Zeyu Zhou , Hui Tian , Ximing Shao , Hongchang Li , Lijing Fang , Ke Liu

Plasma membrane proteins at cell surface are critical for numerous physiological and pathological processes and are primary targets for clinical drugs. Given that clustering of plasma membrane proteins by endogenous stimuli or pharmaceutical interventions serves as a key trigger for their internalization and degradation, this process critically influences their function and turnover. Inspired by this natural process, we developed a modular, protein-of-interest (POI) targeting degradation strategy by using a bifunctional chimera molecule composed of a POI-binding ligand and a self-assembling peptide (WIII/YIII). We term this strategy SAILTAC (Self-Assembling Peptide Induced Lysosomal Targeting Chimera) and demonstrate that these chimeras could efficiently degrade membrane-anchored GFP and the therapeutically relevant immune checkpoint PD-L1. An optimized dimeric chimera (YIII-BMS)₂ potently reduced PD-L1 across multiple cancer cell lines through the lysosomal pathway. Collectively, the SAILTAC strategy offers a versatile and targeted approach to degrade plasma membrane proteins, providing a new tool for nanomedicine application.

细胞表面的质膜蛋白在许多生理和病理过程中起着至关重要的作用，是临床药物的主要靶点。鉴于内源性刺激或药物干预导致的质膜蛋白聚类是其内化和降解的关键触发因素，这一过程对其功能和转化具有关键影响。受这一自然过程的启发，我们利用由POI结合配体和自组装肽（WIII/YIII）组成的双功能嵌合体分子，开发了一种模块化的感兴趣蛋白（POI）靶向降解策略。我们将这种策略命名为SAILTAC（自组装肽诱导溶酶体靶向嵌合体），并证明这些嵌合体可以有效地降解膜锚定的GFP和治疗相关的免疫检查点PD-L1。优化的二聚体嵌合体（ii - bms） 2通过溶酶体途径在多种癌细胞系中有效降低PD-L1。总的来说，SAILTAC策略提供了一种多功能和有针对性的方法来降解质膜蛋白，为纳米医学应用提供了新的工具。

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引用次数: 0

Synthesis and antitumor activity of derivatives of SKF-83566 SKF-83566衍生物的合成及抗肿瘤活性研究

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-08 DOI: 10.1016/j.bmcl.2025.130502

Xiu-Jun Wang , Meng-Xin Lu , Qiu-yue Jin , Zi-Yan Lang , Ming-Li Yang , Jing Ji

In this study, five novel SKF-83566 derivatives (8a–8e) were synthesized by covalently linking pomalidomide to SKF-83566, which features a benzazepine skeleton, via flexible linker chains. Their structures were confirmed using ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry. The antiproliferative activity against HeLa (cervical cancer) and MDA-MB-231 (breast cancer) cells was evaluated using the MTT assay, with SKF-83566, pomalidomide, and 5-fluorouracil (5-FU) serving as controls. The results indicate that most derivatives demonstrated superior activity compared to the control drug, with compound 8a exhibiting the highest potency: an IC₅₀ of 5.50 ± 0.28 μM against MDA-MB-231 cells and 10.13 ± 0.95 μM against HeLa cells. Further experiments demonstrated that 8a inhibits MDA-MB-231 cell colony formation, adhesion, and migration in a concentration-dependent manner, exhibiting a stronger anti-migration effect than 5-Fu. In the MDA-MB-231 cell chicken embryo chorioallantoic membrane (CAM) xenograft model, 8a also showed superior tumor growth inhibition compared to 5-Fu. Structure-activity relationship analysis shows that pomalidomide can enhance the compound's cytotoxicity and targeting ability, while flexible alkyl chains improve cell permeability and target binding capacity. This study confirms that compound 8a has the potential to become a candidate drug for breast cancer treatment, providing a foundation for the development of new antitumor therapies.

本研究通过柔性连接链将pomalidomide与SKF-83566共价连接，合成了5个新的SKF-83566衍生物（8a-8e）， SKF-83566具有苯氮卓类骨架。它们的结构通过1H NMR， 13C NMR和高分辨率质谱进行了证实。以SKF-83566、pomalidomide和5-氟尿嘧啶（5-FU）作为对照，采用MTT法评估其对HeLa（宫颈癌）和MDA-MB-231（乳腺癌）细胞的抗增殖活性。结果表明，与对照药物相比，大多数衍生物表现出更好的活性，化合物8a表现出最高的效力：对MDA-MB-231细胞的IC₅₀为5.50 ± 0.28 μM，对HeLa细胞的IC₅₀为10.13 ± 0.95 μM。进一步实验表明，8a以浓度依赖性的方式抑制MDA-MB-231细胞集落形成、粘附和迁移，表现出比5-Fu更强的抗迁移作用。在MDA-MB-231细胞鸡胚绒毛膜-尿囊膜（CAM）异种移植模型中，与5-Fu相比，8a也表现出更好的肿瘤生长抑制作用。构效关系分析表明，泊马度胺可增强化合物的细胞毒性和靶向能力，而柔性烷基链可提高细胞通透性和靶向结合能力。本研究证实了化合物8a具有成为乳腺癌治疗候选药物的潜力，为开发新的抗肿瘤疗法提供了基础。

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引用次数: 0

A potent and selective RORγ inhibitor for the treatment of autoimmune diseases 一种治疗自身免疫性疾病的有效和选择性的RORγ抑制剂。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-08 DOI: 10.1016/j.bmcl.2025.130494

Taku Ikenogami , Masahiro Yokota , Shingo Fujioka , Naoki Ogawa , Masato Noguchi , Akihiro Nomura , Tsuyoshi Adachi , Yoshiaki Katsuda , Kojo Arita , Naoki Miyagawa , Yusuke Aratsu , Kota Asahina , Paul Crowe , Haiyan Tao , Scott Thacher , Makoto Shiozaki

Retinoic acid receptor-related orphan receptor γ (RORγ) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical role in Th17 cell function and cytokine production makes it a promising therapeutic target for autoimmune diseases. As a result of our high-throughput screening (HTS) campaign to discover novel chemotypes, we identified Cpd 1, a dihydropyrimidinone scaffold with desirable drug-like properties, including favorable ligand efficiency (LE) and fraction of sp³ carbons (Fsp³). Initial structure–activity relationship (SAR) exploration led to the identification of Cpd 17. Target specificity studies of Cpd 17 indicated high selectivity characteristics for the dihydropyrimidinone scaffold. Subsequent X-ray structural analysis revealed its binding mode against RORγ, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd 21, which exhibited significantly improved RORγ inhibitory potency along with LE, and Fsp³ compared to Cpd 1. These results highlight Cpd 21 as a promising lead compound to explore a novel clinical candidate for the development of RORγ-targeted therapies.

视黄酸受体相关孤儿受体γ (RORγ)是Th17细胞分化以及促炎细胞因子如IL-17和IL-22产生的主要转录调节因子。它在Th17细胞功能和细胞因子产生中的关键作用使其成为自身免疫性疾病的有希望的治疗靶点。由于我们的高通量筛选（HTS）活动发现新的化学型，我们确定了cpd1，一种具有理想的药物样特性的二氢嘧啶支架，包括有利的配体效率（LE）和sp3碳的分数（Fsp3）。初步构效关系（SAR）鉴定出Cpd - 17。靶特异性研究表明cpd17对二氢嘧啶支架具有高选择性。随后的x射线结构分析揭示了其与RORγ的结合模式，从而通过基于结构的药物设计（SBDD）进一步优化。这些努力最终鉴定出Cpd 21，与Cpd 1相比，Cpd 21与LE和Fsp3一起表现出显著提高的RORγ抑制能力。这些结果突出了Cpd 21作为一种有前景的先导化合物，可以探索一种新的临床候选物，用于开发ror γ靶向治疗。

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引用次数: 0