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Fused tricyclic pyrrolizinones that exhibit pseudo-irreversible blockade of the NK 1 receptor

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

Bioorganic & Medicinal Chemistry Letters, 2010, Vol.20(19), pp.5925-5932 [Peer Reviewed Journal]

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  • Title:
    Fused tricyclic pyrrolizinones that exhibit pseudo-irreversible blockade of the NK 1 receptor
  • Author: Morriello, Gregori J. ; Chicchi, Gary ; Johnson, Tricia ; Mills, Sander G. ; Demartino, Julie ; Kurtz, Marc ; Tsao, K.L.C. ; Zheng, Song ; Tong, Xinchun ; Carlson, Emma ; Townson, Karen ; Wheeldon, Alan ; Boyce, Susan ; Collinson, Neil ; Rupniak, Nadia ; Devita, Robert J.
  • Description: Previously, we had disclosed a novel class of hNK 1 antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK 1 affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK 1 compounds and to improve functional activity, we have designed and synthesized a new class of hNK 1 antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK 1 antagonists maintain subnanomolar hNK 1 binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK 1 binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID 50 of 0.02 mpk at both 0 and 24 h, respectively. Previously, we had disclosed a novel class of hNK 1 antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK 1 affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK 1 compounds and to improve functional activity, we have designed and synthesized a new class of hNK 1 antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK 1 antagonists maintain subnanomolar hNK 1 binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK 1 binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID 50 of 0.02 mpk at both 0 and 24 h, respectively.
  • Is Part Of: Bioorganic & Medicinal Chemistry Letters, 2010, Vol.20(19), pp.5925-5932
  • Identifier: ISSN: 0960-894X ; DOI: 10.1016/j.bmcl.2010.07.058
  • Subjects: Neurokinin ; Neurokinin-1 Antagonists ; Functional Ip
  • Language: English

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