Discovery and development of a novel N-(3-bromophenyl)-{[(phenylcarbamoyl)amino]methyl}-N-hydroxythiophene-2-carboximidamide indoleamine 2,3-dioxygenase inhibitor using knowledge-based drug design
| Autor: | Teng-Kuang Yeh, Jen-Shin Song, Po-Wei Chang, Jin-Chen Yu, Chia-Hwa Chang, Fang-Yu Liao, Ya-Wen Tien, Ramajayam Kuppusamy, An-Siou Li, Chi-Han Chen, Chieh-Wen Chen, Li-Mei Lin, Hsin-Huei Chang, Chih-Hsiang Huang, Jau-Ying Yao, Mine-Hsine Wu, Yi-Hui Peng, Ching-Cheng Hsueh, Wen-Chi Hsiao, Pei-Husan Chen, Chin-Yu Lin, Su-Huei Hsieh, Chuan Shih, Ming-Shiu Hung, Su-Ying Wu, Ching-Chuan Kuo, Shau-Hua Ueng |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Mice Inbred ICR Binding Sites Organic Chemistry Transplantation Heterologous General Medicine Thiophenes Amides Molecular Docking Simulation Mice Structure-Activity Relationship Cell Line Tumor Drug Design Neoplasms Drug Discovery Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Enzyme Inhibitors Half-Life |
| Zdroj: | European journal of medicinal chemistry. 229 |
| ISSN: | 1768-3254 |
| Popis: | Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1. |
| Databáze: | OpenAIRE |
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