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Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK 1 antagonists

Morriello, Gregori J. ; Mills, Sander G. ; Johnson, Tricia ; Reibarkh, Mikhail ; Chicchi, Gary ; Demartino, Julie ; Kurtz, Marc ; Davies, P. ; Tsao, K.L.C. ; Zheng, Song ; Tong, Xinchun ; Carlson, Emma ; Townson, Karen ; Tattersall, F.D. ; Wheeldon, Alan ; Boyce, Susan ; Collinson, Neil ; Rupniak, Nadia ; Moore, Stephen ; Devita, Robert J.

Bioorganic & Medicinal Chemistry Letters, 2010, Vol.20(6), pp.2007-2012 [Peer Reviewed Journal]

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  • Title:
    Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK 1 antagonists
  • Author: Morriello, Gregori J. ; Mills, Sander G. ; Johnson, Tricia ; Reibarkh, Mikhail ; Chicchi, Gary ; Demartino, Julie ; Kurtz, Marc ; Davies, P. ; Tsao, K.L.C. ; Zheng, Song ; Tong, Xinchun ; Carlson, Emma ; Townson, Karen ; Tattersall, F.D. ; Wheeldon, Alan ; Boyce, Susan ; Collinson, Neil ; Rupniak, Nadia ; Moore, Stephen ; Devita, Robert J.
  • Description: Previous work on human NK 1 (hNK 1) 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 hNK 1 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 ID 50’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. Previous work on human NK 1 (hNK 1) 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 hNK 1 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 ID 50’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.
  • Is Part Of: Bioorganic & Medicinal Chemistry Letters, 2010, Vol.20(6), pp.2007-2012
  • Identifier: ISSN: 0960-894X ; DOI: 10.1016/j.bmcl.2010.01.065
  • Subjects: Neurokinin-1 Antagonist ; Nuerokinin Receptor ; Substance P
  • Language: English

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