Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

Tomoyuki Ohe; Ryutaro Umezawa; Yumina Kitagawara; Daisuke Yasuda; Kyoko Takahashi; Shigeo Nakamura; Akiko Abe; Shuichi Sekine; Kousei Ito; Kentaro Okunushi; Hanae Morio; Tomomi Furihata; Naohiko Anzai; Tadahiko Mashino

doi:10.1016/j.bmcl.2018.10.023

Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

Tomoyuki Ohe, Ryutaro Umezawa, Yumina Kitagawara, Daisuke Yasuda, Kyoko Takahashi, Shigeo Nakamura, Akiko Abe, Shuichi Sekine, Kousei Ito, Kentaro Okunushi, Hanae Morio, Tomomi Furihata, Naohiko Anzai, Tadahiko Mashino

School of Pharmaceutical Sciences

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

7 Citations (Scopus)

Abstract

We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.

Original language	English
Pages (from-to)	3708-3711
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	23-24
DOIs	https://doi.org/10.1016/j.bmcl.2018.10.023
Publication status	Published - 2018 Dec 15

Keywords

Benzbromarone
Hepatotoxicity
Metabolic activation
URAT1

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2018.10.023

Cite this

Ohe, T., Umezawa, R., Kitagawara, Y., Yasuda, D., Takahashi, K., Nakamura, S., Abe, A., Sekine, S., Ito, K., Okunushi, K., Morio, H., Furihata, T., Anzai, N., & Mashino, T. (2018). Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation. Bioorganic and Medicinal Chemistry Letters, 28(23-24), 3708-3711. https://doi.org/10.1016/j.bmcl.2018.10.023

Ohe, T, Umezawa, R, Kitagawara, Y, Yasuda, D, Takahashi, K, Nakamura, S, Abe, A, Sekine, S, Ito, K, Okunushi, K, Morio, H, Furihata, T, Anzai, N & Mashino, T 2018, 'Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 23-24, pp. 3708-3711. https://doi.org/10.1016/j.bmcl.2018.10.023

@article{a2105a77b1cb45a7a13d086f5aaaf72e,

title = "Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation",

abstract = "We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.",

keywords = "Benzbromarone, Hepatotoxicity, Metabolic activation, URAT1",

author = "Tomoyuki Ohe and Ryutaro Umezawa and Yumina Kitagawara and Daisuke Yasuda and Kyoko Takahashi and Shigeo Nakamura and Akiko Abe and Shuichi Sekine and Kousei Ito and Kentaro Okunushi and Hanae Morio and Tomomi Furihata and Naohiko Anzai and Tadahiko Mashino",

note = "Funding Information: This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Japan Agency for Medical Research and Development (AMED; 2012-2016), and the Platform Project for Supporting Drug Discovery and Life Science Research , AMED (2017-2018). This work was also supported by JSPS KAKENHI (Grant Number 16K08379 ) and a special grant generously provided by the Hoansha Foundation. Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2018",

month = dec,

day = "15",

doi = "10.1016/j.bmcl.2018.10.023",

language = "English",

volume = "28",

pages = "3708--3711",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "23-24",

}

TY - JOUR

T1 - Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

AU - Ohe, Tomoyuki

AU - Umezawa, Ryutaro

AU - Kitagawara, Yumina

AU - Yasuda, Daisuke

AU - Takahashi, Kyoko

AU - Nakamura, Shigeo

AU - Abe, Akiko

AU - Sekine, Shuichi

AU - Ito, Kousei

AU - Okunushi, Kentaro

AU - Morio, Hanae

AU - Furihata, Tomomi

AU - Anzai, Naohiko

AU - Mashino, Tadahiko

N1 - Funding Information: This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Japan Agency for Medical Research and Development (AMED; 2012-2016), and the Platform Project for Supporting Drug Discovery and Life Science Research , AMED (2017-2018). This work was also supported by JSPS KAKENHI (Grant Number 16K08379 ) and a special grant generously provided by the Hoansha Foundation. Publisher Copyright: © 2018 Elsevier Ltd

PY - 2018/12/15

Y1 - 2018/12/15

N2 - We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.

AB - We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.

KW - Benzbromarone

KW - Hepatotoxicity

KW - Metabolic activation

KW - URAT1

UR - http://www.scopus.com/inward/record.url?scp=85055697971&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055697971&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2018.10.023

DO - 10.1016/j.bmcl.2018.10.023

M3 - Article

C2 - 30389287

AN - SCOPUS:85055697971

VL - 28

SP - 3708

EP - 3711

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 23-24

ER -

Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this