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

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
Journal	Bioorganic and Medicinal Chemistry Letters
DOIs	https://doi.org/10.1016/j.bmcl.2018.10.023
Publication status	Accepted/In press - 2018 Jan 1

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Keywords

Benzbromarone
Hepatotoxicity
Metabolic activation
URAT1

ASJC Scopus subject areas

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

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. (Accepted/In press). Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation. Bioorganic and Medicinal Chemistry Letters. https://doi.org/10.1016/j.bmcl.2018.10.023

Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation. / Ohe, Tomoyuki; Umezawa, Ryutaro; Kitagawara, Yumina; Yasuda, Daisuke; Takahashi, Kyoko; Nakamura, Shigeo; Abe, Akiko; Sekine, Shuichi; Ito, Kousei; Okunushi, Kentaro; Morio, Hanae; Furihata, Tomomi; Anzai, Naohiko; Mashino, Tadahiko.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2018.

Research output: Contribution to journal › Article

Ohe, Tomoyuki ; Umezawa, Ryutaro ; Kitagawara, Yumina ; Yasuda, Daisuke ; Takahashi, Kyoko ; Nakamura, Shigeo ; Abe, Akiko ; Sekine, Shuichi ; Ito, Kousei ; Okunushi, Kentaro ; Morio, Hanae ; Furihata, Tomomi ; Anzai, Naohiko ; Mashino, Tadahiko. / Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation. In: Bioorganic and Medicinal Chemistry Letters. 2018.

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Access to Document

10.1016/j.bmcl.2018.10.023