Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation
[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 designe...
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| Published in | Bioorganic & medicinal chemistry letters Vol. 28; no. 23-24; pp. 3708 - 3711 |
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| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
OXFORD
Elsevier Ltd
15.12.2018
Elsevier |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0960-894X 1464-3405 1464-3405 |
| DOI | 10.1016/j.bmcl.2018.10.023 |
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| Abstract | [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. |
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| AbstractList | 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. [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. 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.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. |
| Author | Takahashi, Kyoko Abe, Akiko Sekine, Shuichi Ito, Kousei Furihata, Tomomi Umezawa, Ryutaro Nakamura, Shigeo Yasuda, Daisuke Anzai, Naohiko Mashino, Tadahiko Ohe, Tomoyuki Morio, Hanae Kitagawara, Yumina Okunushi, Kentaro |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30389287$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1021/tx7001228 10.1124/dmd.117.077818 10.1248/jhs.53.552 10.2174/138161205774913318 10.1002/jbt.21946 10.1006/abbi.1994.1185 10.2165/00002018-200831080-00002 10.1016/j.toxlet.2011.03.010 10.1007/s12576-011-0136-0 10.1016/0040-4039(95)01611-K 10.1124/dmd.115.065037 10.1097/ACI.0000000000000070 10.1016/j.taap.2015.06.018 10.1016/S0168-8278(94)80011-1 10.1146/annurev.med.58.072905.160823 |
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| Keywords | 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 |
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| References | Miura, Anzai, Jutabha (b0085) 2011; 61 Masseoud, Rott, Liu-Bryan, Agudelo (b0015) 2005; 11 Wang, Peng, Zhang (b0045) 2017; 45 Ohe, Mashino, Hirobe (b0060) 1997; 25 Nakamura, Tezuka, Ushiyama (b0075) 2011; 203 Yoshida, Cho, Akita, Kobayashi (b0040) 2017; 31 Kitagawara, Ohe, Tachibana, Takahashi, Nakamura, Mashino (b0030) 2015; 43 Ulrich (b0005) 2007; 58 Lee, Graham, Williams, Day (b0025) 2008; 31 McDonald, Rettie (b0035) 2007; 20 Tezuka, Takahashi, Suzuki (b0070) 2007; 53 Stephens, Andrade, Lucena (b0010) 2014; 14 Shirakawa, Sekine, Tanaka, Horie, Ito (b0080) 2015; 288 Ohe, Mashino, Hirobe (b0055) 1995; 42 van der Klauw, Houtman, Stricker, Spoelstra (b0020) 1994; 20 Ohe, Mashino, Hirobe (b0050) 1994; 310 Ohe, Hirobe, Mashino (b0065) 2000; 28 Miura (10.1016/j.bmcl.2018.10.023_b0085) 2011; 61 Ohe (10.1016/j.bmcl.2018.10.023_b0065) 2000; 28 Ohe (10.1016/j.bmcl.2018.10.023_b0060) 1997; 25 Ulrich (10.1016/j.bmcl.2018.10.023_b0005) 2007; 58 Yoshida (10.1016/j.bmcl.2018.10.023_b0040) 2017; 31 Ohe (10.1016/j.bmcl.2018.10.023_b0055) 1995; 42 McDonald (10.1016/j.bmcl.2018.10.023_b0035) 2007; 20 Lee (10.1016/j.bmcl.2018.10.023_b0025) 2008; 31 Masseoud (10.1016/j.bmcl.2018.10.023_b0015) 2005; 11 van der Klauw (10.1016/j.bmcl.2018.10.023_b0020) 1994; 20 Ohe (10.1016/j.bmcl.2018.10.023_b0050) 1994; 310 Shirakawa (10.1016/j.bmcl.2018.10.023_b0080) 2015; 288 Tezuka (10.1016/j.bmcl.2018.10.023_b0070) 2007; 53 Stephens (10.1016/j.bmcl.2018.10.023_b0010) 2014; 14 Kitagawara (10.1016/j.bmcl.2018.10.023_b0030) 2015; 43 Wang (10.1016/j.bmcl.2018.10.023_b0045) 2017; 45 Nakamura (10.1016/j.bmcl.2018.10.023_b0075) 2011; 203 Nakamura, S (WOS:000291372900012) 2011; 203 VANDERKLAUW, MM (WOS:A1994NN43000011) 1994; 20 Yoshida, M (WOS:000412328200006) 2017; 31 OHE, T (WOS:A1994NH39200016) 1994; 310 Ulrich, RG (WOS:000244461500002) 2007; 58 McDonald, MG (WOS:000251733400013) 2007; 20 Stephens, C (WOS:000338126900004) 2014; 14 Shirakawa, M (WOS:000362145600002) 2015; 288 Wang, H (WOS:000417069500016) 2017; 45 Lee, MHH (WOS:000258684600002) 2008; 31 Kitagawara, Y (WOS:000358988300002) 2015; 43 Miura, D (WOS:000289858800010) 2011; 61 OHE, T (WOS:A1995RZ29500028) 1995; 36 Tezuka, Y (WOS:000250790000007) 2007; 53 Ohe, T (WOS:000084929800003) 2000; 28 Ohe, T (WOS:A1997WD60800017) 1997; 25 Masseoud, D (WOS:000233419400002) 2005; 11 |
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•Synthesis of a novel set of benzbromarone derivatives.•Reduced cytotoxicity in mouse hepatocytes.•Attenuated mitochondrial toxicity with... We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and... |
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| SubjectTerms | Benzbromarone Chemistry Chemistry, Medicinal Chemistry, Organic Hepatotoxicity Life Sciences & Biomedicine Metabolic activation Pharmacology & Pharmacy Physical Sciences Science & Technology URAT1 |
| Title | Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation |
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