| Autor: |
Andrew J, Kassick, Jinlong, Jiang, Jaime, Bunda, David, Wilson, Jianming, Bao, Huagang, Lu, Peter, Lin, Richard G, Ball, George A, Doss, Xinchun, Tong, Kwei-Lan C, Tsao, Hong, Wang, Gary, Chicchi, Bindhu, Karanam, Richard, Tschirret-Guth, Koppara, Samuel, Donald F, Hora, Sanjeev, Kumar, Maria, Madeira, Waisi, Eng, Richard, Hargreaves, Mona, Purcell, Liza, Gantert, Jacquelyn, Cook, Robert J, DeVita, Sander G, Mills |
| Rok vydání: |
2013 |
| Předmět: |
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| Zdroj: |
Journal of medicinal chemistry. 56(14) |
| ISSN: |
1520-4804 |
| 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 penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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