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Tetrahydroindolizinone NK1 antagonists |
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| Authors: | Jianming Bao Huagang Lu Gregori J Morriello Emma J Carlson Alan Wheeldon Gary G Chicchi Marc M Kurtz Kwei-Lan C Tsao Song Zheng Xinchun Tong Sander G Mills Robert J DeVita |
| Institution: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA;2. Department In Vivo Neuroscience, Merck Research Laboratories, Rahway, NJ 07065, USA;3. Department Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA;4. Department Immunology and Rheumatology, Merck Research Laboratories, Rahway, NJ 07065, USA |
| Abstract: | 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. |
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