2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one: A Potent Human NK1 Receptor Antagonist with Multiple Clearance Pathways
| Autor: | David Wilson, Bindhu V. Karanam, Mona Purcell, Maria Madeira, Gary G. Chicchi, Jianming Bao, Liza Gantert, Robert J. DeVita, Huagang Lu, Wai-Si Eng, Sander G. Mills, Richard G. Ball, Andrew J. Kassick, Peter Lin, Sanjeev Kumar, Jaime Lynn Bunda, George A. Doss, Kwei-Lan C. Tsao, Jacquelyn J. Cook, Xinchun Tong, Richard Tschirret-Guth, Jinlong Jiang, Koppara Samuel, Richard Hargreaves, Hong Wang, Donald F. Hora |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 56:5940-5948 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug–drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug–drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetrati... |
| Databáze: | OpenAIRE |
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