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, Satoshi; Ito, Kousei; Okunushi, Kentaro; Morio, Hanae; Furihata, Tomomi; Anzai, Naohiko; Mashino, Tadahiko

doi:10.1016/j.bmcl.2018.10.023

Cited by 9 publications

(6 citation statements)

References 15 publications

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“…All the target compounds were evaluated for their URAT1 inhibitory activities in HEK293-URAT1 cells using 14 C-labeled uric acid as the substrate. The activity data are listed in Tables 1 and 2.…”

Section: In Vitro Evaluation and Structure-activity Relationshipsmentioning

confidence: 99%

“…Although it is much more effective than Probenecid, occurrence of liver toxicity has been occasionally reported. Therefore, liver function monitoring is required when prescribing this drug [9,13,14]. Lesinurad is a relatively weak URAT1 inhibitor with an IC 50 at micromolar level.…”

Section: Introductionmentioning

confidence: 99%

“…To identify novel URAT1 inhibitors with better therapeutic profiles, we exploited a pharmacophore fusion strategy based on the structures of Telmisartan and Epaminurad (Figure 3). It was reported that the 3,5-dibromo-4-hydroxyphenyl fragment might be responsible for metabolic activation and resultant hepatic toxicity of Benzbromarone derivatives [14]. The biphenyl carboxylic acid fragment from Telmisartan was thus taken as the anionic component, while fragments similar to the 3,4-dihydro-2H-pyrido [4,3-b] [1,4]oxazine part in Epaminurad were introduced as the hydrophobic component.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors

Hou,

Wang,

Yang

et al. 2023

Molecules

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Urate transporter 1 (URAT1) is a clinically validated target for the treatment of hyperuricemia and gout. Due to the absence of protein structures, the molecular design of new URAT1 inhibitors generally resorts to ligand-based approaches. Two series of biphenyl carboxylic acids were designed based on the structures of URAT1 inhibitors Epaminurad and Telmisartan via a strategy of pharmacophore fusion. Fifty-one novel compounds were synthesized and most of them showed obvious inhibition against human URAT1. A1 and B21 were identified as the most potent URAT1 inhibitors in series A and B, respectively. They exhibited IC50 values of 0.93 μM and 0.17 μM, which were comparable or superior to the clinical uricosuric drug benzbromarone. The results confirmed the effectiveness of ligand-based approaches in identifying novel and potent URAT1 inhibitors.

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Section: In Vitro Evaluation and Structure-activity Relationshipsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors

Hou,

Wang,

Yang

et al. 2023

Molecules

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“…Apart from the above molecules, several pharmaceutical drugs contain the aroyl benzofuran structural core. For instance, Benzbromarone is a 3-aroylbenzofuran derivative which acts as a uricosuric agent [9]. However, after the serious side efforts of hepatotoxicity it was withdrawn from the market.…”

Section: Introductionmentioning

confidence: 99%

C–H Functionalization of 2-/3- Aroylbenzofurans: A Tool for Developing New AntiArrhythmic Drugs

Kolluru¹

2022

ACSR

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Aroyl-benzofurans are important heterocyclic compounds which displayed a wide range of biological activities and important structural motif of many pharmaceutical drugs. Most of the pharmaceutical drugs containing the aroyl-benzofuran structural core have severe side effects which limits its usage. Some of the drugs containing the aroyl-benzofuran structural core were withdrawn from the market due to its toxicity. So, there is a need for the development of new synthetic methods to functionalize these molecules which play a significant role in drug discovery program. The current review focuses on the C-H functionalization of 2-/3-aroyl-benzofurans which includes alkylation, arylation, phosphonylation and benzoylation which plays a crucial role in developing new anti-arrhythmic drugs.

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“…Many studies have been carried out to investigate the mechanisms of BBR-induced hepatic toxicity − including the involvement of metabolism, metabolites, and mitochondrial toxicity. Among these potential mechanisms, mitochondrial inhibitory activity (MIA) is one of the most promising theories for fulminant hepatitis. , Based on these findings, to obtain compounds that possess potent pharmacological effects without mitochondrial toxicity, we modified BBR to overcome its disadvantages, which may be related to a structural flaw.…”

mentioning

confidence: 99%

Discovery of Dotinurad (FYU-981), a New Phenol Derivative with Highly Potent Uric Acid Lowering Activity

Uda¹,

Kobashi²,

Miyata³

et al. 2020

ACS Med. Chem. Lett.

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To derive new uricosuric agents, novel phenol derivatives were synthesized to overcome the disadvantages of benzbromarone (BBR), attributed by its structural features. Herein, we report the discovery of new phenol derivatives with a 1,1-dioxo-1,2-dihydro-3H-1,3-benzothiazole scaffold. The selected compound 11 (dotinurad, FYU-981) demonstrated remarkable inhibitory activity on uric acid uptake by primary human renal proximal tubule epithelial cells (RPTECs) and URAT1-mediated uric acid transport, with weak inhibitory activity against mitochondrial respiration. Dotinurad also displayed favorable pharmacokinetic profiles and higher potency in decreasing uric acid than BBR did in Cebus monkeys. Dotinurad has been approved as a new uricosuric medicine in Japan. Our strategy, which focuses on the structural features resulting in unfavorable effects, could be applied to the future developments of other drugs with disadvantages, particularly those having a bis-aryl ketone structure.

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Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

Cited by 9 publications

References 15 publications

Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors

Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors

C–H Functionalization of 2-/3- Aroylbenzofurans: A Tool for Developing New AntiArrhythmic Drugs

Discovery of Dotinurad (FYU-981), a New Phenol Derivative with Highly Potent Uric Acid Lowering Activity

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