Tetrahydroindolizinone NK1 antagonists

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

doi:10.1016/j.bmcl.2010.01.120

Tetrahydroindolizinone NK₁ antagonists

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

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

A new class of potent NK₁ 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 NK₁ receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK₁ binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P₄₅₀ inhibition and hPXR induction profiles.

Original language	English
Pages (from-to)	2354-2358
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	7
DOIs	https://doi.org/10.1016/j.bmcl.2010.01.120
State	Published - 1 Apr 2010
Externally published	Yes

Keywords

Antagonists
Gerbil foot tapping
IP1
NK1
Tetrahydroindolizinone

Access to Document

10.1016/j.bmcl.2010.01.120

Cite this

@article{fc154c833d55492aa843bdac3818662a,

title = "Tetrahydroindolizinone NK1 antagonists",

abstract = "A new class of potent NK1 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 NK1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P450 inhibition and hPXR induction profiles.",

keywords = "Antagonists, Gerbil foot tapping, IP1, NK1, Tetrahydroindolizinone",

author = "Jianming Bao and Huagang Lu and Morriello, {Gregori J.} and Carlson, {Emma J.} and Alan Wheeldon and Chicchi, {Gary G.} and Kurtz, {Marc M.} and Tsao, {Kwei Lan C.} and Song Zheng and Xinchun Tong and Mills, {Sander G.} and DeVita, {Robert J.}",

year = "2010",

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doi = "10.1016/j.bmcl.2010.01.120",

language = "English",

volume = "20",

pages = "2354--2358",

journal = "Bioorganic and Medicinal Chemistry Letters",

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TY - JOUR

T1 - Tetrahydroindolizinone NK1 antagonists

AU - Bao, Jianming

AU - Lu, Huagang

AU - Morriello, Gregori J.

AU - Carlson, Emma J.

AU - Wheeldon, Alan

AU - Chicchi, Gary G.

AU - Kurtz, Marc M.

AU - Tsao, Kwei Lan C.

AU - Zheng, Song

AU - Tong, Xinchun

AU - Mills, Sander G.

AU - DeVita, Robert J.

PY - 2010/4/1

Y1 - 2010/4/1

N2 - A new class of potent NK1 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 NK1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P450 inhibition and hPXR induction profiles.

AB - A new class of potent NK1 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 NK1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P450 inhibition and hPXR induction profiles.

KW - Antagonists

KW - Gerbil foot tapping

KW - IP1

KW - NK1

KW - Tetrahydroindolizinone

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DO - 10.1016/j.bmcl.2010.01.120

M3 - Article

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JF - Bioorganic and Medicinal Chemistry Letters

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