skip to main content
Language:
Search Limited to: Search Limited to: Resource type Show Results with: Show Results with: Index

Fused bicyclic pyrrolizinones as new scaffolds for human NK 1 antagonists

Morriello, Gregori J. ; Devita, Robert J. ; Mills, Sander G. ; Young, Jonathan R. ; Lin, Peter ; Doss, George ; Chicchi, Gary G. ; Demartino, Julie ; Kurtz, Marc M. ; Tsao, Kwei-Lan C. ; Carlson, Emma ; Townson, Karen ; Wheeldon, Alan ; Boyce, Susan ; Collinson, Neil ; Rupniak, Nadia ; Moore, Stephen

Bioorganic & Medicinal Chemistry, 2008, Vol.16(5), pp.2156-2170 [Peer Reviewed Journal]

Full text available

View all versions
Citations Cited by
  • Title:
    Fused bicyclic pyrrolizinones as new scaffolds for human NK 1 antagonists
  • Author: Morriello, Gregori J. ; Devita, Robert J. ; Mills, Sander G. ; Young, Jonathan R. ; Lin, Peter ; Doss, George ; Chicchi, Gary G. ; Demartino, Julie ; Kurtz, Marc M. ; Tsao, Kwei-Lan C. ; Carlson, Emma ; Townson, Karen ; Wheeldon, Alan ; Boyce, Susan ; Collinson, Neil ; Rupniak, Nadia ; Moore, Stephen
  • Description: A novel 5,5-fused pyrrolidine scaffold has been discovered which exhibits superior brain penetration and maintains excellent binding affinity, as well as, functional IP activity versus previously reported hNK 1 antagonist. 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.
  • Is Part Of: Bioorganic & Medicinal Chemistry, 2008, Vol.16(5), pp.2156-2170
  • Identifier: ISSN: 0968-0896 ; DOI: 10.1016/j.bmc.2007.11.081
  • Language: English
  • Source: ScienceDirect (Elsevier B.V.)

Searching Remote Databases, Please Wait