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Tetrahydroindolizinone NK 1 antagonists

Bao, Jianming ; Lu, Huagang ; Morriello, Gregori J. ; Carlson, Emma J. ; Wheeldon, Alan ; Chicchi, Gary G. ; Kurtz, Marc M. ; Tsao, Kwei-Lan C. ; Zheng, Song ; Tong, Xinchun ; Mills, Sander G. ; Devita, Robert J.

Bioorganic & Medicinal Chemistry Letters, 2010, Vol.20(7), pp.2354-2358 [Peer Reviewed Journal]

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  • Title:
    Tetrahydroindolizinone NK 1 antagonists
  • Author: Bao, Jianming ; Lu, Huagang ; Morriello, Gregori J. ; Carlson, Emma J. ; Wheeldon, Alan ; Chicchi, Gary G. ; Kurtz, Marc M. ; Tsao, Kwei-Lan C. ; Zheng, Song ; Tong, Xinchun ; Mills, Sander G. ; Devita, Robert J.
  • Description: A new class of potent NK 1 receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK 1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK 1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P 450 inhibition and hPXR induction profiles. A new class of potent NK 1 receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK 1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK 1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P 450 inhibition and hPXR induction profiles .
  • Is Part Of: Bioorganic & Medicinal Chemistry Letters, 2010, Vol.20(7), pp.2354-2358
  • Identifier: ISSN: 0960-894X ; DOI: 10.1016/j.bmcl.2010.01.120
  • Subjects: Tetrahydroindolizinone ; Nk1 ; Antagonists ; Gerbil Foot Tapping ; Ip1
  • Language: English

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