Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase
| Autor: | Zhong Yang, Jay O. Knipe, Susan B. Roberts, Yong Tu, Paul E. Morin, Ying-Kai Wang, John Wan, Andrew Nickel, Katharine A. Grant-Young, Piyasena Hewawasam, Sam T. Chao, Xiaoliang Zhuo, Bergstrom Carl P, Brett R. Beno, Qi Gao, Dianlin Xie, Chong-Hwan Chang, Dawn D. Parker, Mian Gao, Alicia Regueiro-Ren, Mengping Liu, Umesh Hanumegowda, Richard J. Colonno, Kathy Mosure, Nicholas A. Meanwell, Min Ding, Lenore A. Pelosi, John F. Kadow, Xiaofan Zheng, Steven Sheriff, Voss Stacey A, Alicia Ng, Kenneth S. Santone, Mark R. Witmer, Jung-Hui Sun, Robert G. Gentles, Bender John A, Min Gao, Yi Wang, Jeff Tredup, Daniel M. Camac, Scott W. Martin, Thomas W. Hudyma, Julie A. Lemm, Kap-Sun Yeung, Karen Rigat |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Indoles Magnetic Resonance Spectroscopy Membrane permeability Hepatitis C virus Allosteric regulation Viral Nonstructural Proteins Pharmacology medicine.disease_cause Antiviral Agents Mass Spectrometry Structure-Activity Relationship chemistry.chemical_compound Transactivation Dogs Allosteric Regulation Drug Discovery medicine Animals Humans Structure–activity relationship Enzyme Inhibitors Beclabuvir Pregnane X receptor Drug discovery Benzazepines Rats Biochemistry chemistry Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 57:1855-1879 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm4016894 |
| Popis: | Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation. |
| Databáze: | OpenAIRE |
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