Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors
Urate transporter 1 (URAT1) is a clinically validated target for the treatment of hyperuricemia and gout. Due to the absence of protein structures, the molecular design of new URAT1 inhibitors generally resorts to ligand-based approaches. Two series of biphenyl carboxylic acids were designed based o...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/21/7415 |
| _version_ | 1797631578648608768 |
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| author | Xianxin Hou Yongcheng Wang Yajun Yang Zhiyan Xiao |
| author_facet | Xianxin Hou Yongcheng Wang Yajun Yang Zhiyan Xiao |
| author_sort | Xianxin Hou |
| collection | DOAJ |
| description | Urate transporter 1 (URAT1) is a clinically validated target for the treatment of hyperuricemia and gout. Due to the absence of protein structures, the molecular design of new URAT1 inhibitors generally resorts to ligand-based approaches. Two series of biphenyl carboxylic acids were designed based on the structures of URAT1 inhibitors Epaminurad and Telmisartan via a strategy of pharmacophore fusion. Fifty-one novel compounds were synthesized and most of them showed obvious inhibition against human URAT1. <b>A1</b> and <b>B21</b> were identified as the most potent URAT1 inhibitors in series A and B, respectively. They exhibited IC<sub>50</sub> values of 0.93 μM and 0.17 μM, which were comparable or superior to the clinical uricosuric drug benzbromarone. The results confirmed the effectiveness of ligand-based approaches in identifying novel and potent URAT1 inhibitors. |
| first_indexed | 2024-03-11T11:24:32Z |
| format | Article |
| id | doaj.art-a11c36f86e214955837e6c712be7f7a3 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T11:24:32Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a11c36f86e214955837e6c712be7f7a32023-11-10T15:08:56ZengMDPI AGMolecules1420-30492023-11-012821741510.3390/molecules28217415Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 InhibitorsXianxin Hou0Yongcheng Wang1Yajun Yang2Zhiyan Xiao3Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaBeijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaBeijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaBeijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaUrate transporter 1 (URAT1) is a clinically validated target for the treatment of hyperuricemia and gout. Due to the absence of protein structures, the molecular design of new URAT1 inhibitors generally resorts to ligand-based approaches. Two series of biphenyl carboxylic acids were designed based on the structures of URAT1 inhibitors Epaminurad and Telmisartan via a strategy of pharmacophore fusion. Fifty-one novel compounds were synthesized and most of them showed obvious inhibition against human URAT1. <b>A1</b> and <b>B21</b> were identified as the most potent URAT1 inhibitors in series A and B, respectively. They exhibited IC<sub>50</sub> values of 0.93 μM and 0.17 μM, which were comparable or superior to the clinical uricosuric drug benzbromarone. The results confirmed the effectiveness of ligand-based approaches in identifying novel and potent URAT1 inhibitors.https://www.mdpi.com/1420-3049/28/21/7415URAT1biphenyl carboxylic acidhyperuricemiagout |
| spellingShingle | Xianxin Hou Yongcheng Wang Yajun Yang Zhiyan Xiao Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors Molecules URAT1 biphenyl carboxylic acid hyperuricemia gout |
| title | Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors |
| title_full | Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors |
| title_fullStr | Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors |
| title_full_unstemmed | Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors |
| title_short | Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors |
| title_sort | discovery of novel biphenyl carboxylic acid derivatives as potent urat1 inhibitors |
| topic | URAT1 biphenyl carboxylic acid hyperuricemia gout |
| url | https://www.mdpi.com/1420-3049/28/21/7415 |
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