Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 23-24; pp. 3708 - 3711
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2018; Elsevier
• Subjects: Benzbromarone; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Hepatotoxicity; Life Sciences & Biomedicine; Metabolic activation; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; URAT1; Benzbromarone; DBH; MPT; LDH; DBBQ; BBR; hURAT1; URAT1; DEX; IDR; CAT; Metabolic activation; CYP; Hepatotoxicity; CYTOCHROME-P450; PATHWAY; PHENOLS; IPSO-SUBSTITUTION; BIOACTIVATION; ELIMINATION; OXYGEN-ATOM
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2018.10.023

[Display omitted] •Synthesis of a novel set of benzbromarone derivatives.•Reduced cytotoxicity in mouse hepatocytes.•Attenuated mitochondrial toxicity with metabolic activation.•Maintained activity of inhibition toward uric acid transporter. 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.