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Substituted fused bicyclic pyrrolizinones as potent,orally bioavailable hNK1 antagonists |
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| Authors: | Gregori J Morriello Sander G Mills Tricia Johnson Mikhail Reibarkh Gary Chicchi Julie DeMartino Marc Kurtz P Davies KLC Tsao Song Zheng Xinchun Tong Emma Carlson Karen Townson FD Tattersall Alan Wheeldon Susan Boyce Neil Collinson Nadia Rupniak Stephen Moore Robert J DeVita |
| Institution: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA;2. Department of Immunology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA;3. Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA;4. Department of Behavioral Neuroscience, Merck Research Laboratories, Terlings Park, UK |
| Abstract: | Previous work on human NK1 (hNK1) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural–activity-relationship studies on simple α- and β-substituted compounds of this series provided several potent and bioavailable hNK1 antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24 h with ID50’s of less than 1 mpk. One particular α-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity. |
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