Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain

被引：129

作者：

Chowdhury, Sultan ^{[1
]}

Chafeev, Mikhail ^{[1
]}

Liu, Shifeng ^{[1
]}

Sun, Jianyu ^{[1
]}

Raina, Vandna ^{[1
]}

Chui, Ray ^{[2
]}

Young, Wendy ^{[2
]}

Kwan, Rainbow ^{[2
]}

Fu, Jianmin ^{[1
]}

Cadieux, Jay A. ^{[1
]}

机构：

[1] Xenon Pharmaceut Inc, Dept Med Chem, Burnaby, BC V5G 4W8, Canada

[2] Xenon Pharmaceut Inc, Dept Biol Sci, Burnaby, BC V5G 4W8, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 12期

关键词：

Sodium channel; SCN9A; Pain; Spirooxindole; Oxindole; GATED SODIUM-CHANNELS; MUTATIONS; SCN9A; PHARMACOLOGY; TARGETS; POTENT; FURAN;

D O I：

10.1016/j.bmcl.2011.04.088

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification strategy then led to the discovery of XEN907, a novel spirooxindole Na(V)1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3676 / 3681

页数：6

共 25 条

[11] Pharmacology of 2-[4-(4-chloro-2-fluorophenoxy) phenyl]-pyrimidine-4-carboxamide: A potent, broad-spectrum state-dependent sodium channel blocker for treating pain states [J].

Ilyin, Victor I. ;

Pomonis, James D. ;

Whiteside, Garth T. ;

Harrison, James E. ;

Pearson, Michelle S. ;

Mark, Lilly ;

Turchin, Paul I. ;

Gottshall, Susan ;

Carter, Richard B. ;

Nguyen, Phong ;

Hogenkamp, Derk J. ;

Olanrewaju, Shakira ;

Benjamin, Elfrida ;

Woodward, Richard M. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 318 (03) :1083-1093

[12] THE ALDOL REACTION OF SILYL ENOL ETHERS WITH ALDEHYDES IN AQUEOUS-MEDIA [J].

KOBAYASHI, S ;

HACHIYA, I .

TETRAHEDRON LETTERS, 1992, 33 (12) :1625-1628

[13] Regioselective synthesis of the 3,4-dihydrofuro[3,2-d]pyrimidin-2(1H)-one skeleton: a new class of compound [J].

Koza, Gani ;

Ozcan, Sevil ;

Sahin, Ertan ;

Balci, Metin .

TETRAHEDRON, 2009, 65 (31) :5973-5976

[14] Enantioselective Synthesis of Flavan-3-ols Using a Mitsunobu Cyclization [J].

Krohn, Karsten ;

Ahmed, Ishtiaq ;

John, Markus .

SYNTHESIS-STUTTGART, 2009, (05) :779-786

[15]

KUNIHIRO M, 2002, CHEM PHARM BULL, V50, P298

[16]

Mantegazza M, 2010, LANCET NEUROL, V9, P413, DOI 10.1016/S1474-4422(10)70059-4

[17] A Peripherally Acting Nav1.7 Sodium Channel Blocker Reverses Hyperalgesia and Allodynia on Rat Models of Inflammatory and Neuropathic Pain [J].

McGowan, Erin ;

Hoyt, Scott B. ;

Li, Xiaohua ;

Lyons, Kathryn A. ;

Abbadie, Catherine .

ANESTHESIA AND ANALGESIA, 2009, 109 (03) :951-958

[18] SYNTHESIS OF 7-H-3-(1S,4S)-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-N-METHYL-L-NAPHTHALENAMINE HYDROCHLORIDE (7-H-3-SERTRALINE) [J].

WELCH, WM ;

WILLIAMS, MT .

JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 1993, 33 (02) :119-125

[19] Glutathione trapping to measure microsomal oxidation of furan to cis-2-butene-1,4-dial [J].

Peterson, LA ;

Cummings, ME ;

Vu, CC ;

Matter, BA .

DRUG METABOLISM AND DISPOSITION, 2005, 33 (10) :1453-1458

[20] Electrophilic intermediates produced by bioactivation of furan [J].

Peterson, Lisa A. .

DRUG METABOLISM REVIEWS, 2006, 38 (04) :615-626

← 1 2 3 →