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

Osamu Irie; Takatoshi Kosaka; Masashi Kishida; Junichi Sakaki; Keiichi Masuya; Kazuhide Konishi; Fumiaki Yokokawa; Takeru Ehara; Atsuko Iwasaki; Yuki Iwaki; Yuko Hitomi; Atsushi Toyao; Hiroki Gunji; Naoki Teno; Genji Iwasaki; Hajime Hirao; Takanori Kanazawa; Keiko Tanabe; Peter C. Hiestand; Marzia Malcangio; Alyson J. Fox; Stuart J. Bevan; Mohammed Yaqoob; Andrew J. Culshaw; Terance W. Hart; Allan Hallett

doi:10.1016/j.bmcl.2008.08.067

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

Osamu Irie^*, Takatoshi Kosaka, Masashi Kishida, Junichi Sakaki, Keiichi Masuya, Kazuhide Konishi, Fumiaki Yokokawa, Takeru Ehara, Atsuko Iwasaki, Yuki Iwaki, Yuko Hitomi, Atsushi Toyao, Hiroki Gunji, Naoki Teno, Genji Iwasaki, Hajime Hirao, Takanori Kanazawa, Keiko Tanabe, Peter C. Hiestand, Marzia MalcangioAlyson J. Fox, Stuart J. Bevan, Mohammed Yaqoob, Andrew J. Culshaw, Terance W. Hart, Allan Hallett

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

27 Citations (Scopus)

Abstract

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. © 2008 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	5280-5284
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	19
DOIs	https://doi.org/10.1016/j.bmcl.2008.08.067
Publication status	Published - 1 Oct 2008
Externally published	Yes

Research Keywords

Brain-penetrating
Cathepsin S inhibitor
hERG
Multiple sclerosis
Neuropathic pain

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10.1016/j.bmcl.2008.08.067

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Irie, O., Kosaka, T., Kishida, M., Sakaki, J., Masuya, K., Konishi, K., Yokokawa, F., Ehara, T., Iwasaki, A., Iwaki, Y., Hitomi, Y., Toyao, A., Gunji, H., Teno, N., Iwasaki, G., Hirao, H., Kanazawa, T., Tanabe, K., Hiestand, P. C., ... Hallett, A. (2008). Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-Cyanopyrimidines. Part 2. Bioorganic and Medicinal Chemistry Letters, 18(19), 5280-5284. https://doi.org/10.1016/j.bmcl.2008.08.067

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abstract = "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. {\textcopyright} 2008 Elsevier Ltd. All rights reserved.",

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Irie, O, Kosaka, T, Kishida, M, Sakaki, J, Masuya, K, Konishi, K, Yokokawa, F, Ehara, T, Iwasaki, A, Iwaki, Y, Hitomi, Y, Toyao, A, Gunji, H, Teno, N, Iwasaki, G, Hirao, H, Kanazawa, T, Tanabe, K, Hiestand, PC, Malcangio, M, Fox, AJ, Bevan, SJ, Yaqoob, M, Culshaw, AJ, Hart, TW & Hallett, A 2008, 'Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-Cyanopyrimidines. Part 2', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 19, pp. 5280-5284. https://doi.org/10.1016/j.bmcl.2008.08.067

TY - JOUR

T1 - Overcoming hERG issues for brain-penetrating cathepsin S inhibitors

T2 - 2-Cyanopyrimidines. Part 2

AU - Irie, Osamu

AU - Kosaka, Takatoshi

AU - Kishida, Masashi

AU - Sakaki, Junichi

AU - Masuya, Keiichi

AU - Konishi, Kazuhide

AU - Yokokawa, Fumiaki

AU - Ehara, Takeru

AU - Iwasaki, Atsuko

AU - Iwaki, Yuki

AU - Hitomi, Yuko

AU - Toyao, Atsushi

AU - Gunji, Hiroki

AU - Teno, Naoki

AU - Iwasaki, Genji

AU - Hirao, Hajime

AU - Kanazawa, Takanori

AU - Tanabe, Keiko

AU - Hiestand, Peter C.

AU - Malcangio, Marzia

AU - Fox, Alyson J.

AU - Bevan, Stuart J.

AU - Yaqoob, Mohammed

AU - Culshaw, Andrew J.

AU - Hart, Terance W.

AU - Hallett, Allan

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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. © 2008 Elsevier Ltd. All rights reserved.

AB - 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. © 2008 Elsevier Ltd. All rights reserved.

KW - Brain-penetrating

KW - Cathepsin S inhibitor

KW - hERG

KW - Multiple sclerosis

KW - Neuropathic pain

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U2 - 10.1016/j.bmcl.2008.08.067

DO - 10.1016/j.bmcl.2008.08.067

M3 - RGC 21 - Publication in refereed journal

C2 - 18783943

SN - 0960-894X

VL - 18

SP - 5280

EP - 5284

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 19

ER -

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

Abstract

Research Keywords

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