1. Fused bicyclic pyrrolizinones as new scaffolds for human NK1 antagonists
- Author
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Peter Lin, Gary G. Chicchi, Julie A. DeMartino, Neil Collinson, Marc M. Kurtz, Susan Boyce, Robert J. DeVita, Alan Wheeldon, Jonathan R. Young, Stephen Moore, Emma J. Carlson, Kwei-Lan C. Tsao, Sander G. Mills, Karen Townson, George A. Doss, Gregori J. Morriello, and Nadia M.J. Rupniak
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Hydroxylation ,Methylation ,Biochemistry ,Chemical synthesis ,Pyrrolidine ,chemistry.chemical_compound ,Neurokinin-1 Receptor Antagonists ,In vivo ,Drug Discovery ,Humans ,Urea ,Pyrroles ,Molecular Biology ,Molecular Structure ,Bicyclic molecule ,Chemistry ,Organic Chemistry ,Diastereomer ,Stereoisomerism ,Penetration (firestop) ,Receptors, Neurokinin-1 ,Bridged Bicyclo Compounds, Heterocyclic ,Amides ,In vitro ,Lactam ,Epoxy Compounds ,Molecular Medicine - Abstract
Previous work on human NK(1) antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.
- Published
- 2008
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