Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-Cyanopyrimidines. Part 2

被引：24

作者：

Irie, Osamu ^{[1
]}

Kosaka, Takatoshi ^{[1
]}

Kishida, Masashi ^{[1
]}

Sakaki, Junichi ^{[1
]}

Masuya, Keiichi ^{[1
]}

Konishi, Kazuhide ^{[1
]}

Yokokawa, Fumiaki ^{[1
]}

Ehara, Takeru ^{[1
]}

Iwasaki, Atsuko ^{[1
]}

Iwaki, Yuki ^{[1
]}

Hitomi, Yuko ^{[1
]}

Toyao, Atsushi ^{[1
]}

Gunji, Hiroki ^{[1
]}

Teno, Naoki ^{[1
]}

Iwasaki, Genji ^{[1
]}

Hirao, Hajime ^{[1
]}

Kanazawa, Takanori ^{[1
]}

Tanabe, Keiko ^{[1
]}

Hiestand, Peter C. ^{[2
]}

Malcangio, Marzia ^{[3
]}

Fox, Alyson J. ^{[3
]}

Bevan, Stuart J. ^{[3
]}

Yaqoob, Mohammed ^{[3
]}

Culshaw, Andrew J. ^{[3
]}

Hart, Terance W. ^{[3
]}

Hallett, Allan ^{[3
]}

机构：

[1] Novartis Inst BioMed Res, Tsukuba, Ibaraki 3002611, Japan

[2] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

[3] Novartis Inst BioMed Res, London WC1E 6BS, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 19期

关键词：

cathepsin S inhibitor; brain-penetrating; hERG; multiple sclerosis; neuropathic pain;

D O I：

10.1016/j.bmcl.2008.08.067

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5] non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：5280 / 5284

页数：5

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