Tetrahydroindolizinone NK sub(1) antagonists

Tetrahydroindolizinone NK sub(1) antagonists

A new class of potent NK sub(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 tetrahydroindoliz...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (7), p.2354-2358
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung:A new class of potent NK sub(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 sub(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK sub(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P sub(450) inhibition and hPXR induction profiles. AB:
ISSN:0960-894X
DOI:10.1016/j.bmcl.2010.01.120