Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2)

Yoshinori Ichihara; Ryohei Fujimura; Hiroshi Tsuneki; Tsutomu Wada; Kentaro Okamoto; Hiroaki Gouda; Shuichi Hirono; Kenji Sugimoto; Yuji Matsuya; Toshiyasu Sasaoka; Naoki Toyooka

doi:10.1016/j.ejmech.2013.01.014

Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2)

Yoshinori Ichihara, Ryohei Fujimura, Hiroshi Tsuneki, Tsutomu Wada, Kentaro Okamoto, Hiroaki Gouda, Shuichi Hirono, Kenji Sugimoto, Yuji Matsuya, Toshiyasu Sasaoka, Naoki Toyooka^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Novel 4-substituted 2-pyridin-2-ylamides were developed using in-silico ligand-based drug design (LBDD) in an attempt to identify inhibitors of SH2-containing 5′-inositol phosphatase 2 (SHIP2), which is implicated in insulin-resistant type 2 diabetes. Among the compounds synthesized, N-[4-(4-chlorobenzyloxy)pyridin-2-yl]-2-(2,6-difluorophenyl)- acetamide (CPDA, 4a) was identified as a potent SHIP2 inhibitor. CPDA was found to enhance in vitro insulin signaling through the Akt pathway more efficiently than the previously reported SHIP2 inhibitor AS1949490, and ameliorated abnormal glucose metabolism in diabetic (db/db) mice.

Original language	English
Pages (from-to)	649-660
Number of pages	12
Journal	European Journal of Medicinal Chemistry
Volume	62
DOIs	https://doi.org/10.1016/j.ejmech.2013.01.014
State	Published - 2013/04

Keywords

Ligand-based drug design (LBDD)
N-[4-(4-Chlorobenzyloxy)Pyridin-2-yl]-2-(2,6- difluorophenyl)-acetamide (CPDA)
SH2-containing 5′-inositol phosphatase 2 (SHIP2)

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2013.01.014

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Ichihara, Y., Fujimura, R., Tsuneki, H., Wada, T., Okamoto, K., Gouda, H., Hirono, S., Sugimoto, K., Matsuya, Y., Sasaoka, T., & Toyooka, N. (2013). Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2). European Journal of Medicinal Chemistry, 62, 649-660. https://doi.org/10.1016/j.ejmech.2013.01.014

@article{d873ae8df45345b885c4736c765abcca,

title = "Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2)",

abstract = "Novel 4-substituted 2-pyridin-2-ylamides were developed using in-silico ligand-based drug design (LBDD) in an attempt to identify inhibitors of SH2-containing 5′-inositol phosphatase 2 (SHIP2), which is implicated in insulin-resistant type 2 diabetes. Among the compounds synthesized, N-[4-(4-chlorobenzyloxy)pyridin-2-yl]-2-(2,6-difluorophenyl)- acetamide (CPDA, 4a) was identified as a potent SHIP2 inhibitor. CPDA was found to enhance in vitro insulin signaling through the Akt pathway more efficiently than the previously reported SHIP2 inhibitor AS1949490, and ameliorated abnormal glucose metabolism in diabetic (db/db) mice.",

keywords = "Ligand-based drug design (LBDD), N-[4-(4-Chlorobenzyloxy)Pyridin-2-yl]-2-(2,6- difluorophenyl)-acetamide (CPDA), SH2-containing 5′-inositol phosphatase 2 (SHIP2)",

author = "Yoshinori Ichihara and Ryohei Fujimura and Hiroshi Tsuneki and Tsutomu Wada and Kentaro Okamoto and Hiroaki Gouda and Shuichi Hirono and Kenji Sugimoto and Yuji Matsuya and Toshiyasu Sasaoka and Naoki Toyooka",

note = "Funding Information: This study was supported, in part, by a Grant from Japan Science and Technology Agency and the First Bank of Toyama Foundation (to T.S.). We thank A. Nakano for technical assistance with the screening assay. ",

year = "2013",

month = apr,

doi = "10.1016/j.ejmech.2013.01.014",

language = "英語",

volume = "62",

pages = "649--660",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

}

Ichihara, Y, Fujimura, R, Tsuneki, H , Wada, T, Okamoto, K, Gouda, H, Hirono, S, Sugimoto, K, Matsuya, Y , Sasaoka, T & Toyooka, N 2013, 'Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2)', European Journal of Medicinal Chemistry, vol. 62, pp. 649-660. https://doi.org/10.1016/j.ejmech.2013.01.014

TY - JOUR

T1 - Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2)

AU - Ichihara, Yoshinori

AU - Fujimura, Ryohei

AU - Tsuneki, Hiroshi

AU - Wada, Tsutomu

AU - Okamoto, Kentaro

AU - Gouda, Hiroaki

AU - Hirono, Shuichi

AU - Sugimoto, Kenji

AU - Matsuya, Yuji

AU - Sasaoka, Toshiyasu

AU - Toyooka, Naoki

N1 - Funding Information: This study was supported, in part, by a Grant from Japan Science and Technology Agency and the First Bank of Toyama Foundation (to T.S.). We thank A. Nakano for technical assistance with the screening assay.

PY - 2013/4

Y1 - 2013/4

N2 - Novel 4-substituted 2-pyridin-2-ylamides were developed using in-silico ligand-based drug design (LBDD) in an attempt to identify inhibitors of SH2-containing 5′-inositol phosphatase 2 (SHIP2), which is implicated in insulin-resistant type 2 diabetes. Among the compounds synthesized, N-[4-(4-chlorobenzyloxy)pyridin-2-yl]-2-(2,6-difluorophenyl)- acetamide (CPDA, 4a) was identified as a potent SHIP2 inhibitor. CPDA was found to enhance in vitro insulin signaling through the Akt pathway more efficiently than the previously reported SHIP2 inhibitor AS1949490, and ameliorated abnormal glucose metabolism in diabetic (db/db) mice.

AB - Novel 4-substituted 2-pyridin-2-ylamides were developed using in-silico ligand-based drug design (LBDD) in an attempt to identify inhibitors of SH2-containing 5′-inositol phosphatase 2 (SHIP2), which is implicated in insulin-resistant type 2 diabetes. Among the compounds synthesized, N-[4-(4-chlorobenzyloxy)pyridin-2-yl]-2-(2,6-difluorophenyl)- acetamide (CPDA, 4a) was identified as a potent SHIP2 inhibitor. CPDA was found to enhance in vitro insulin signaling through the Akt pathway more efficiently than the previously reported SHIP2 inhibitor AS1949490, and ameliorated abnormal glucose metabolism in diabetic (db/db) mice.

KW - Ligand-based drug design (LBDD)

KW - N-[4-(4-Chlorobenzyloxy)Pyridin-2-yl]-2-(2,6- difluorophenyl)-acetamide (CPDA)

KW - SH2-containing 5′-inositol phosphatase 2 (SHIP2)

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DO - 10.1016/j.ejmech.2013.01.014

M3 - 学術論文

C2 - 23434638

AN - SCOPUS:84874136774

SN - 0223-5234

VL - 62

SP - 649

EP - 660

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2)

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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