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PXR Antagonists

详细技术说明

Nuclear receptors such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenobiotic receptors that regulate not only drug metabolism and disposition but also various huma

*Abstract

Nuclear receptors such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenobiotic receptors that regulate not only drug metabolism and disposition but also various human diseases such as cancer, diabetes, inflammatory disease, metabolic disease and liver diseases, suggesting that PXR and CAR are promising targets for drug discovery. Consequently, there is an urgent need to discover and develop small molecules that target these PXR- and/or CAR-mediated human-disease- related pathways for relevant therapeutic applications. Researchers at St. Jude have invented potent specific and non-toxic modulators (agonists and antagonists) of the PXR; synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of modulating an adverse drug reaction in a mammal using the compounds (PXR antagonists) and pharmaceutical compositions; methods of treatment of a disorder of uncontrolled cellular proliferation, such as a cancer, using the compounds (PXR antagonists) and pharmaceutical compositions; methods of modulating pregnane X receptor activity in a mammal using the compounds and pharmaceutical compositions. These compounds (PXR antagonists) should improve efficacy of co-administered drugs, particularly cancer drugs, by inhibiting multi-drug resistance; and/or be used as a co-therapy to prevent therapy-related toxicities, drug-drug interactions, and drug resistance, and improve therapeutic efficacy and safety. Related Scientific ReferencesWenwei Lin, Yue-Ming Wang, Sergio C. Chai, Lili Lv, Jie Zheng, Jing Wu, Qijun Zhang, Yong-Dong Wang, Patrick R. Griffin & Taosheng Chen, SPA70 is a potent antagonist of human pregnane X receptor. Nature Communications, 8: 741, 2017, DOI: 10.1038/s41467-017-00780-5, http://rdcu.be/wi5zLin W, Goktug AN, Wu J, Currier DG, and Chen T. High-throughput screening identifies 1,4,5-substituted 1,2,3-triazole analogs as potent and specific antagonists of pregnane X receptor. Assay Drug Dev Technol 2017 Nov 7. doi: 10.1089/adt.2017.809. [Epub ahead of print]. http://bit.ly/2md6C2k Chen, et al., Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor, European Journal of Medicinal Chemistry 108 (2016) 505-528 http://www.sciencedirect.com/science/journal/02235234/108/supp/CCherian MT, Lin W, Wu J, Chen T., CINPA1 is an inhibitor of constitutive androstane receptor (CAR) that does not activate pregnane X receptor (PXR). Mol Pharmacol 87(5): 878-889, 2015.

国家/地区

美国