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Discovery of a Phosphodiesterase 7A Inhibitor of High Isozyme Selectivity Exhibiting In Vivo Anti-Osteoporotic Effects. 高同工酶选择性磷酸二酯酶7A抑制剂的体内抗骨质疏松作用的发现。
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-27 eCollection Date: 2025-01-09 DOI: 10.1021/acsmedchemlett.4c00570
Kentaro Kondo, Kazuki Otake, Tetsudo Kaya, Shohei Miwa, Yoshifumi Ueyama, Tsunemitsu Haruta, Jun Nishihata, Takashi Nakagawa, Nobuhide Azuma, Kayoko Takagi, Toshiki Urashima, Yuki Kitao, Makoto Shiozaki

Phosphodiesterases (PDEs) have drawn attention due to their critical roles in physiological and pathological conditions. Many research groups have studied these hydrolytic enzymes to develop new drugs, including apremilast as a PDE4 inhibitor and sildenafil as a PDE5 inhibitor. Targeting PDE7 has also been deemed a rational strategy to ameliorate autoimmune conditions. However, to date, no successful clinical results have been reported. We postulated that progress in these studies with PDE7 had been hampered by the lack of a potent ligand with a reasonable selectivity for this PDE isozyme. Therefore, starting from a PDE7A/7B dual inhibitor, our investigations led to improved selectivity along with extended metabolic stability, resulting in a novel PDE7A inhibitor 26. This compound with high selectivity over the closest isozyme is an ideal chemical entity to unveil new pharmacological roles of PDE7A-dependent signaling, as exemplified by the in vivo antiosteoporotic effects.

磷酸二酯酶(PDEs)因其在生理和病理过程中的重要作用而备受关注。许多研究小组已经研究了这些水解酶来开发新药,包括作为PDE4抑制剂的阿普雷米司特和作为PDE5抑制剂的西地那非。靶向PDE7也被认为是改善自身免疫性疾病的一种合理策略。然而,到目前为止,还没有成功的临床结果报告。我们假设PDE7的研究进展受到缺乏对PDE同工酶具有合理选择性的有效配体的阻碍。因此,从PDE7A/7B双抑制剂开始,我们的研究导致了选择性的提高和代谢稳定性的延长,从而产生了一种新的PDE7A抑制剂26。该化合物对最接近的同工酶具有高选择性,是揭示pde7a依赖性信号新药理作用的理想化学实体,例如体内抗骨质疏松作用。
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引用次数: 0
Discovery of a Phosphodiesterase 7A Inhibitor of High Isozyme Selectivity Exhibiting In Vivo Anti-Osteoporotic Effects
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-26 DOI: 10.1021/acsmedchemlett.4c0057010.1021/acsmedchemlett.4c00570
Kentaro Kondo, Kazuki Otake, Tetsudo Kaya, Shohei Miwa, Yoshifumi Ueyama, Tsunemitsu Haruta, Jun Nishihata, Takashi Nakagawa, Nobuhide Azuma, Kayoko Takagi, Toshiki Urashima, Yuki Kitao and Makoto Shiozaki*, 

Phosphodiesterases (PDEs) have drawn attention due to their critical roles in physiological and pathological conditions. Many research groups have studied these hydrolytic enzymes to develop new drugs, including apremilast as a PDE4 inhibitor and sildenafil as a PDE5 inhibitor. Targeting PDE7 has also been deemed a rational strategy to ameliorate autoimmune conditions. However, to date, no successful clinical results have been reported. We postulated that progress in these studies with PDE7 had been hampered by the lack of a potent ligand with a reasonable selectivity for this PDE isozyme. Therefore, starting from a PDE7A/7B dual inhibitor, our investigations led to improved selectivity along with extended metabolic stability, resulting in a novel PDE7A inhibitor 26. This compound with high selectivity over the closest isozyme is an ideal chemical entity to unveil new pharmacological roles of PDE7A-dependent signaling, as exemplified by the in vivo antiosteoporotic effects.

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引用次数: 0
Tetrazole Is a Novel Zinc Binder Chemotype for Carbonic Anhydrase Inhibition. 四唑是一种抑制碳酸酐酶的新型锌结合剂化学型。
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-25 eCollection Date: 2025-01-09 DOI: 10.1021/acsmedchemlett.4c00562
Simone Giovannuzzi, Andrea Angeli, Paloma Begines, Marta Ferraroni, Alessio Nocentini, Claudiu T Supuran

The tetrazole group is here proposed as a zinc-binding warhead for the inhibition of the metalloenzyme carbonic anhydrases. A set of synthesized derivatives incorporating the tetrazole moiety were evaluated as inhibitors against a panel of human isoforms, exhibiting K I values spanning between the submicromolar and low-to-medium micromolar ranges (0.62-19.6 μM). X-ray crystallographic studies were conducted to gain insights into their modes of binding to the target enzyme. These findings mark a significant advancement in the search for inhibitory chemotypes other than classical sulfonamides.

本文提出了四唑基团作为锌结合战斗部,用于抑制金属酶碳酸酐酶。一组含有四氮唑片段的合成衍生物被评估为人类同种异构体的抑制剂,其K I值在亚微摩尔和低至中微摩尔范围(0.62-19.6 μM)之间。进行了x射线晶体学研究,以深入了解它们与靶酶的结合模式。这些发现标志着在寻找除经典磺胺类药物以外的抑制性化学型方面取得了重大进展。
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引用次数: 0
Tetrazole Is a Novel Zinc Binder Chemotype for Carbonic Anhydrase Inhibition
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-25 DOI: 10.1021/acsmedchemlett.4c0056210.1021/acsmedchemlett.4c00562
Simone Giovannuzzi*, Andrea Angeli, Paloma Begines, Marta Ferraroni, Alessio Nocentini and Claudiu T. Supuran*, 

The tetrazole group is here proposed as a zinc-binding warhead for the inhibition of the metalloenzyme carbonic anhydrases. A set of synthesized derivatives incorporating the tetrazole moiety were evaluated as inhibitors against a panel of human isoforms, exhibiting KI values spanning between the submicromolar and low-to-medium micromolar ranges (0.62–19.6 μM). X-ray crystallographic studies were conducted to gain insights into their modes of binding to the target enzyme. These findings mark a significant advancement in the search for inhibitory chemotypes other than classical sulfonamides.

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引用次数: 0
Expanding the Chemical Space of Reverse Fosmidomycin Analogs. 拓展反向磷霉素类似物的化学空间。
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-23 eCollection Date: 2025-01-09 DOI: 10.1021/acsmedchemlett.4c00501
Talea Knak, Sana Takada, Boris Illarionov, Violetta Krisilia, Lais Pessanha de Carvalho, Beate Lungerich, Yasumitsu Sakamoto, Stefan Höfmann, Adelbert Bacher, Rainer Kalscheuer, Jana Held, Markus Fischer, Nobutada Tanaka, Thomas Kurz

Multidrug-resistant pathogens pose a major threat to human health, necessitating the identification of new drug targets and lead compounds that are not susceptible to cross-resistance. This study demonstrates that novel reverse thia analogs of the phosphonohydroxamic acid antibiotic fosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme for Plasmodium falciparum, Escherichia coli, and Mycobacterium tuberculosis that is absent in humans. Some novel analogs with large α-phenyl substituents exhibited strong inhibition across these three DXR orthologues, surpassing the inhibitory activity of fosmidomycin. Despite nanomolar target inhibition, the new DXR inhibitors demonstrated mainly weak or no in vitro growth inhibition of the pathogens. Crystallographic studies revealed that compounds 12a and 12b induce an open PfDXR conformation and that the enzyme selectively binds the S-enantiomers. The study underscores the difficulties of achieving potent cellular activity despite strong DXR inhibition and emphasizes the need for novel structural optimization strategies and comprehensive pharmacokinetic studies.

耐多药病原体对人类健康构成重大威胁,因此有必要确定不容易产生交叉耐药性的新药物靶点和先导化合物。该研究表明,磷羟肟酸抗生素fosmidomycin的新型反向类似物可抑制1-脱氧-d-木糖5-磷酸还原异构酶(DXR), DXR是恶性疟原虫,大肠杆菌和结核分枝杆菌的必需酶,在人类中不存在。一些具有大α-苯基取代基的新型类似物对这三个DXR同源物表现出强烈的抑制作用,超过了fosmidomycin的抑制活性。尽管具有纳摩尔靶抑制作用,但新型DXR抑制剂对病原菌的体外生长抑制作用较弱或无抑制作用。晶体学研究表明,化合物12a和12b诱导了一个开放的PfDXR构象,并且酶选择性地结合s -对映体。该研究强调了尽管有很强的DXR抑制,但实现有效细胞活性的困难,并强调需要新的结构优化策略和全面的药代动力学研究。
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引用次数: 0
N-Arylsulfonylated C-Homoaporphines as a New Class of Antiplatelet and Antimicrobial Agents
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-23 DOI: 10.1021/acsmedchemlett.4c0049110.1021/acsmedchemlett.4c00491
Bharti Rajesh Kumar Shyamlal, Amol T. Mahajan, Vikash Kumar, Aarohi Gupta, Rishabh Shrivastava Ronin, Manas Mathur, Janmejaya Sen and Sandeep Chaudhary*, 

A series of novel N-arylsulfonylated C-homoaporphine alkaloids were synthesized under microwave irradiation and evaluated for their in vitro antiplatelet and antimicrobial activities. Among the series, compounds 12a, 12c, 12e, 12f, 12h, 12j, 12k, 12m, and 12o demonstrated highly potent (∼3-fold) platelet aggregation inhibitory activity than acetylsalicylic acid (IC50 = 21.34 μg/mL). Several N-arylsulfonylated C-homoaporphines also exhibited promising antimicrobial activity against various strains, including Macrophoma phaseolina, Trichoderma reesei, and Aspergillus niger, with minimum inhibitory concentrations (MIC) of 12.5, 6.25, and 12.5 μg/mL, respectively, comparable to Ketoconazole [MIC = 12.5 μg/mL (MP and AN strain); 6.25 μg/mL (TR strain)]. 12h showed potent antibacterial activity (IC50 = 6.25 μg/mL against Escherichia coli and Bacillus subtilis) compared to Ampicillin (IC50 = 12.5 μg/mL). After thorough structure–activity relationship (SAR) and in silico studies, C-homoaporphines were identified as a novel class of antiplatelet and antimicrobial agents.

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引用次数: 0
Discovery of a Potent Triazole-Based Reversible Targeted Covalent Inhibitor of Cruzipain. 一种有效的三唑基可逆性靶向共价克鲁铂抑制剂的发现。
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-23 eCollection Date: 2025-01-09 DOI: 10.1021/acsmedchemlett.4c00460
Juan Pablo Cerutti, Lucas Abreu Diniz, Viviane Corrêa Santos, Salomé Catalina Vilchez Larrea, Guillermo Daniel Alonso, Rafaela Salgado Ferreira, Mario Alfredo Quevedo, Wim Dehaen

Cruzipain (CZP) is an essential cysteine protease of Trypanosoma cruzi, the etiological agent of Chagas disease, and a promising druggable target. To date, no CZP inhibitors have reached clinical use, with research efforts mostly hampered by insufficient potency, limited target selectivity or lack of bioactivity translation from the isolated enzyme to the parasite in cellular environments. In this study, we report the design of SH-1, a 1,2,3-triazole-based targeted covalent inhibitor with nanomolar potency (IC50 = 28 nM) and null inhibition of human cathepsin L. SH-1 demonstrates bioactivity translation comparable to that of K777 (1-10 μM), a CZP inhibitor previously advanced to clinical trials. Experimental findings indicate that SH-1 forms a reversible covalent bond with Cys25 in CZP, while in silico and structure-activity relationship studies suggest that this interaction is guided by acid-base equilibrium dynamics. The potential of SH-1 for preclinical development is discussed alongside detailed structure-activity relationships for the further optimization of CZP inhibitors.

克氏锥虫蛋白酶(CZP)是恰加斯病的病原克氏锥虫必需的半胱氨酸蛋白酶,是一种很有前景的药物靶点。迄今为止,还没有CZP抑制剂达到临床应用,研究工作主要受到效力不足、目标选择性有限或缺乏从分离酶到细胞环境中寄生虫的生物活性翻译的阻碍。在这项研究中,我们报道了SH-1的设计,SH-1是一种基于1,2,3-三唑的靶向共价抑制剂,具有纳米摩尔效价(IC50 = 28 nM),对人组织蛋白酶l无抑制作用。SH-1的生物活性翻译与K777 (1-10 μM)相当,K777是一种已经进入临床试验的CZP抑制剂。实验结果表明,SH-1在CZP中与Cys25形成可逆共价键,而硅和构效关系研究表明,这种相互作用受酸碱平衡动力学的指导。讨论了SH-1在临床前开发中的潜力,以及详细的结构-活性关系,以进一步优化CZP抑制剂。
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引用次数: 0
N-Arylsulfonylated C-Homoaporphines as a New Class of Antiplatelet and Antimicrobial Agents. n -芳基磺酰化c -同源阿啡作为一类新的抗血小板和抗菌药物。
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-23 eCollection Date: 2025-01-09 DOI: 10.1021/acsmedchemlett.4c00491
Bharti Rajesh Kumar Shyamlal, Amol T Mahajan, Vikash Kumar, Aarohi Gupta, Rishabh Shrivastava Ronin, Manas Mathur, Janmejaya Sen, Sandeep Chaudhary

A series of novel N-arylsulfonylated C-homoaporphine alkaloids were synthesized under microwave irradiation and evaluated for their in vitro antiplatelet and antimicrobial activities. Among the series, compounds 12a, 12c, 12e, 12f, 12h, 12j, 12k, 12m, and 12o demonstrated highly potent (∼3-fold) platelet aggregation inhibitory activity than acetylsalicylic acid (IC50 = 21.34 μg/mL). Several N-arylsulfonylated C-homoaporphines also exhibited promising antimicrobial activity against various strains, including Macrophoma phaseolina, Trichoderma reesei, and Aspergillus niger, with minimum inhibitory concentrations (MIC) of 12.5, 6.25, and 12.5 μg/mL, respectively, comparable to Ketoconazole [MIC = 12.5 μg/mL (MP and AN strain); 6.25 μg/mL (TR strain)]. 12h showed potent antibacterial activity (IC50 = 6.25 μg/mL against Escherichia coli and Bacillus subtilis) compared to Ampicillin (IC50 = 12.5 μg/mL). After thorough structure-activity relationship (SAR) and in silico studies, C-homoaporphines were identified as a novel class of antiplatelet and antimicrobial agents.

在微波辐照下合成了一系列新型n -芳基磺化C-homoaporphine生物碱,并对其体外抗血小板和抗菌活性进行了评价。其中,化合物12a、12c、12e、12f、12h、12j、12k、12m和12o比乙酰水杨酸具有更强的抑制血小板聚集活性(IC50 = 21.34 μg/mL)(约3倍)。几种n -芳基磺化的c -同型萘啡对菜绿大瘤、里氏木霉和黑曲霉等多种菌株也表现出良好的抑菌活性,其最低抑菌浓度(MIC)分别为12.5、6.25和12.5 μg/mL,与酮康唑[MIC = 12.5 μg/mL (MP和AN菌株)]相当;6.25 μg/mL (TR菌株)]。与氨苄西林(IC50 = 12.5 μg/mL)相比,12h对大肠杆菌和枯草芽孢杆菌具有较强的抑菌活性(IC50 = 6.25 μg/mL)。经过深入的构效关系(SAR)和硅研究,C-homoaporphines被确定为一类新的抗血小板和抗菌药物。
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引用次数: 0
Expanding the Chemical Space of Reverse Fosmidomycin Analogs
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-22 DOI: 10.1021/acsmedchemlett.4c0050110.1021/acsmedchemlett.4c00501
Talea Knak, Sana Takada, Boris Illarionov, Violetta Krisilia, Lais Pessanha de Carvalho, Beate Lungerich, Yasumitsu Sakamoto, Stefan Höfmann, Adelbert Bacher, Rainer Kalscheuer, Jana Held, Markus Fischer, Nobutada Tanaka* and Thomas Kurz*, 

Multidrug-resistant pathogens pose a major threat to human health, necessitating the identification of new drug targets and lead compounds that are not susceptible to cross-resistance. This study demonstrates that novel reverse thia analogs of the phosphonohydroxamic acid antibiotic fosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme for Plasmodium falciparum, Escherichia coli, and Mycobacterium tuberculosis that is absent in humans. Some novel analogs with large α-phenyl substituents exhibited strong inhibition across these three DXR orthologues, surpassing the inhibitory activity of fosmidomycin. Despite nanomolar target inhibition, the new DXR inhibitors demonstrated mainly weak or no in vitro growth inhibition of the pathogens. Crystallographic studies revealed that compounds 12a and 12b induce an open PfDXR conformation and that the enzyme selectively binds the S-enantiomers. The study underscores the difficulties of achieving potent cellular activity despite strong DXR inhibition and emphasizes the need for novel structural optimization strategies and comprehensive pharmacokinetic studies.

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引用次数: 0
Discovery of a Potent Triazole-Based Reversible Targeted Covalent Inhibitor of Cruzipain
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-12-22 DOI: 10.1021/acsmedchemlett.4c0046010.1021/acsmedchemlett.4c00460
Juan Pablo Cerutti, Lucas Abreu Diniz, Viviane Corrêa Santos, Salomé Catalina Vilchez Larrea, Guillermo Daniel Alonso, Rafaela Salgado Ferreira, Mario Alfredo Quevedo* and Wim Dehaen*, 

Cruzipain (CZP) is an essential cysteine protease of Trypanosoma cruzi, the etiological agent of Chagas disease, and a promising druggable target. To date, no CZP inhibitors have reached clinical use, with research efforts mostly hampered by insufficient potency, limited target selectivity or lack of bioactivity translation from the isolated enzyme to the parasite in cellular environments. In this study, we report the design of SH-1, a 1,2,3-triazole-based targeted covalent inhibitor with nanomolar potency (IC50 = 28 nM) and null inhibition of human cathepsin L. SH-1 demonstrates bioactivity translation comparable to that of K777 (1–10 μM), a CZP inhibitor previously advanced to clinical trials. Experimental findings indicate that SH-1 forms a reversible covalent bond with Cys25 in CZP, while in silico and structure–activity relationship studies suggest that this interaction is guided by acid–base equilibrium dynamics. The potential of SH-1 for preclinical development is discussed alongside detailed structure–activity relationships for the further optimization of CZP inhibitors.

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引用次数: 0
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ACS Medicinal Chemistry Letters
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