4-Amino-2-cyanopyrimidines: Novel scaffold for nonpeptidic cathepsin S inhibitors

Osamu Irie; Fumiaki Yokokawa; Takeru Ehara; Atsuko Iwasaki; Yuki Iwaki; Yuko Hitomi; Kazuhide Konishi; Masashi Kishida; Atsushi Toyao; Keiichi Masuya; Hiroki Gunji; Junichi Sakaki; Genji Iwasaki; Hajime Hirao; Takanori Kanazawa; Keiko Tanabe; Takatoshi Kosaka; Terance W. Hart; Allan Hallett

doi:10.1016/j.bmcl.2008.07.011

4-Amino-2-cyanopyrimidines: Novel scaffold for nonpeptidic cathepsin S inhibitors

Osamu Irie^*, Fumiaki Yokokawa, Takeru Ehara, Atsuko Iwasaki, Yuki Iwaki, Yuko Hitomi, Kazuhide Konishi, Masashi Kishida, Atsushi Toyao, Keiichi Masuya, Hiroki Gunji, Junichi Sakaki, Genji Iwasaki, Hajime Hirao, Takanori Kanazawa, Keiko Tanabe, Takatoshi Kosaka, Terance W. Hart, Allan Hallett

^*Corresponding author for this work

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

19 Citations (Scopus)

Abstract

We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine. © 2008 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	4642-4646
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2008.07.011
Publication status	Published - 15 Aug 2008
Externally published	Yes

Research Keywords

Cathepsin S inhibitors
Cysteine protease
Nitrile
Pyrimidine

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10.1016/j.bmcl.2008.07.011

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Irie, O., Yokokawa, F., Ehara, T., Iwasaki, A., Iwaki, Y., Hitomi, Y., Konishi, K., Kishida, M., Toyao, A., Masuya, K., Gunji, H., Sakaki, J., Iwasaki, G., Hirao, H., Kanazawa, T., Tanabe, K., Kosaka, T., Hart, T. W., & Hallett, A. (2008). 4-Amino-2-cyanopyrimidines: Novel scaffold for nonpeptidic cathepsin S inhibitors. Bioorganic and Medicinal Chemistry Letters, 18(16), 4642-4646. https://doi.org/10.1016/j.bmcl.2008.07.011

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title = "4-Amino-2-cyanopyrimidines: Novel scaffold for nonpeptidic cathepsin S inhibitors",

abstract = "We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine. {\textcopyright} 2008 Elsevier Ltd. All rights reserved.",

keywords = "Cathepsin S inhibitors, Cysteine protease, Nitrile, Pyrimidine",

author = "Osamu Irie and Fumiaki Yokokawa and Takeru Ehara and Atsuko Iwasaki and Yuki Iwaki and Yuko Hitomi and Kazuhide Konishi and Masashi Kishida and Atsushi Toyao and Keiichi Masuya and Hiroki Gunji and Junichi Sakaki and Genji Iwasaki and Hajime Hirao and Takanori Kanazawa and Keiko Tanabe and Takatoshi Kosaka and Hart, {Terance W.} and Allan Hallett",

year = "2008",

month = aug,

day = "15",

doi = "10.1016/j.bmcl.2008.07.011",

language = "English",

volume = "18",

pages = "4642--4646",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd.",

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Irie, O, Yokokawa, F, Ehara, T, Iwasaki, A, Iwaki, Y, Hitomi, Y, Konishi, K, Kishida, M, Toyao, A, Masuya, K, Gunji, H, Sakaki, J, Iwasaki, G, Hirao, H, Kanazawa, T, Tanabe, K, Kosaka, T, Hart, TW & Hallett, A 2008, '4-Amino-2-cyanopyrimidines: Novel scaffold for nonpeptidic cathepsin S inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 16, pp. 4642-4646. https://doi.org/10.1016/j.bmcl.2008.07.011

TY - JOUR

T1 - 4-Amino-2-cyanopyrimidines

T2 - Novel scaffold for nonpeptidic cathepsin S inhibitors

AU - Irie, Osamu

AU - Yokokawa, Fumiaki

AU - Ehara, Takeru

AU - Iwasaki, Atsuko

AU - Iwaki, Yuki

AU - Hitomi, Yuko

AU - Konishi, Kazuhide

AU - Kishida, Masashi

AU - Toyao, Atsushi

AU - Masuya, Keiichi

AU - Gunji, Hiroki

AU - Sakaki, Junichi

AU - Iwasaki, Genji

AU - Hirao, Hajime

AU - Kanazawa, Takanori

AU - Tanabe, Keiko

AU - Kosaka, Takatoshi

AU - Hart, Terance W.

AU - Hallett, Allan

PY - 2008/8/15

Y1 - 2008/8/15

N2 - We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine. © 2008 Elsevier Ltd. All rights reserved.

AB - We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine. © 2008 Elsevier Ltd. All rights reserved.

KW - Cathepsin S inhibitors

KW - Cysteine protease

KW - Nitrile

KW - Pyrimidine

UR - http://www.scopus.com/inward/record.url?scp=48649093235&partnerID=8YFLogxK

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-48649093235&origin=recordpage

U2 - 10.1016/j.bmcl.2008.07.011

DO - 10.1016/j.bmcl.2008.07.011

M3 - RGC 21 - Publication in refereed journal

C2 - 18662880

SN - 0960-894X

VL - 18

SP - 4642

EP - 4646

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 16

ER -

4-Amino-2-cyanopyrimidines: Novel scaffold for nonpeptidic cathepsin S inhibitors

Abstract

Research Keywords

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