Tetrahydroindolizinone NK1 antagonists

被引：5

作者：

Bao, Jianming ^{[1
]}

Lu, Huagang ^{[1
]}

Morriello, Gregori J. ^{[1
]}

Carlson, Emma J. ^{[2
]}

Wheeldon, Alan ^{[2
]}

Chicchi, Gary G. ^{[4
]}

Kurtz, Marc M. ^{[4
]}

Tsao, Kwei-Lan C. ^{[4
]}

Zheng, Song ^{[3
]}

Tong, Xinchun ^{[3
]}

Mills, Sander G. ^{[1
]}

DeVita, Robert J. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept In Vivo Neurosci, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Immunol & Rheumatol, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 07期

关键词：

Tetrahydroindolizinone; NK1; Antagonists; Gerbil foot tapping; IP1; RECEPTOR ANTAGONIST; POTENT; OXADIAZOLES;

D O I：

10.1016/j.bmcl.2010.01.120

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 P-450 inhibition and hPXR induction profiles. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2354 / 2358

页数：5

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