Tetrahydroindolizinone NK1 antagonists
| Autor: | Gary G. Chicchi, Kwei-Lan C. Tsao, Huagang Lu, Xinchun Tong, Gregori J. Morriello, Robert J. DeVita, Alan Wheeldon, Emma J. Carlson, Sander G. Mills, Song Zheng, Jianming Bao, Marc M. Kurtz |
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| Rok vydání: | 2009 |
| Předmět: |
Chemistry
Stereochemistry Organic Chemistry Clinical Biochemistry Indolizines Pharmaceutical Science Receptors Neurokinin-1 Gerbil Biochemistry Pyrrolidine chemistry.chemical_compound Structure-Activity Relationship Neurokinin-1 Receptor Antagonists In vivo Drug Discovery Molecular Medicine Functional activity Animals Humans Receptor Selectivity Gerbillinae Molecular Biology |
| Zdroj: | Bioorganicmedicinal chemistry letters. 20(7) |
| ISSN: | 1464-3405 |
| Popis: | A new class of potent NK1 receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P450 inhibition and hPXR induction profiles. |
| Databáze: | OpenAIRE |
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