Design, synthesis, and biological studies of dual URAT1 inhibitor and FXR agonist based on benzbromarone

Huang, Wanqiu; Jiao, Shixuan; Chen, Siliang; Chen, Ya; Yang, Zhigang; Wang, Wenxin; Cao, Zhijun; Li, Zheng; Zhang, Luyong

doi:10.1016/j.bmc.2022.117073

Cited by 3 publications

(3 citation statements)

References 24 publications

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“…Mechanistically it is thought that FXR-mediated inhibition of the NLRP3 inflammasome will decrease gout-associated inflammation, while URAT1 inhibition will function as a uricosuric, enhancing uric acid excretion in the urine. 678 The dual modulator ZLY28 (Guangdong Pharmaceutical University) was discovered to both be a gut-restricted FXR agonist and Fatty Acid Binding Protein 1 (FABP1) antagonist. FABP1 is essential for lipid chaperoning and the gut-mediated absorption of fatty acids.…”

Section: Druggable Targets Ba Pharmacology Fxr Modulatorsmentioning

confidence: 99%

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Fleishman,

Kumar

2024

Sig Transduct Target Ther

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Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.

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Section: Druggable Targets Ba Pharmacology Fxr Modulatorsmentioning

confidence: 99%

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Fleishman,

Kumar

2024

Sig Transduct Target Ther

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“…So far, various multitarget compounds have been developed to lower SUA levels, including URAT1/XO inhibitors, 32,33 URAT1/glucose transporter 9 (GLUT9) inhibitors, 34 URAT1/XO/GLUT9 inhibitors, 35 and URAT1 inhibitor/farnesoid X receptor (FXR) agonist. 36 XO/URAT1 dual inhibition represents a synergetic approach to effectively reduce SUA levels from a mechanistic perspective (Figure 1). Despite promising initial results, PF-06743649 (structure undisclosed), a potential XO/URAT1 dual inhibitor, was discontinued in clinical development due to identified renal safety concerns.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of a Potent and Orally Bioavailable Xanthine Oxidase/Urate Transporter 1 Dual Inhibitor as a Potential Treatment for Hyperuricemia and Gout

Yang,

Li,

Pan

et al. 2024

J. Med. Chem.

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The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat (2) and the URAT1 inhibitor probenecid (3), followed by structure–activity relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (XO IC50 = 35 nM; URAT1 IC50 = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound 27 emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.

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“…Lifestyle changes and the strict control of the intake of purine-rich foods such as meat, seafood, and animal organs can alleviate the symptoms of hyperuricemia [22][23][24]. Furthermore, some drugs such as allopurinol, benzbromarone, pegalogenase, and losartan can also participate in the treatment of hyperuricemia by inhibiting the synthesis of UA or promoting the degradation and excretion of UA [25][26][27][28]. However, the above-mentioned drugs may cause various degrees of side effects and cannot achieve the expected effect of clinical treatment [29].…”

Section: Introductionmentioning

confidence: 99%

Biodegradation of Inosine and Guanosine by Bacillus paranthracis YD01

Du,

Jiang,

Sun

et al. 2023

IJMS

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Both inosine and guanosine are precursors of uric acid that may cause the diseases of hyperuricemia and gout in humans. Here, a promising bacterial strain for efficiently biodegrading both inosine and guanosine was successfully isolated from a healthy human intestine and identified as Bacillus paranthracis YD01 with 16S rRNA analysis. An initial amount of 49.6 mg·L−1 of inosine or 49.9 mg·L−1 of guanosine was completely removed by YD01 within 12 h, which showed that YD01 had a strong ability to biodegrade inosine and guanosine. Furthermore, the initial amount of 49.2 mg·L−1 of inosine or 49.5 mg·L−1 of guanosine was totally catalyzed by the intracellular crude enzymes of YD01 within 6 h, and the initial inosine amount of 49.6 mg·L−1 or guanosine of 49.7 mg·L−1 was biodegraded by the extracellular crude enzymes of YD01 within 9 h. Illumina Hiseq sequencing and database gene annotation were used to elucidate the genomic characteristics of B. paranthracis YD01. Purine nucleoside phosphorylase, encoded by gene 1785, gene 3933, and gene 4403, was found in the KEEG database, which played a crucial role in the biodegradation of inosine and guanosine. The results of this study provide valuable insights into the mechanisms for biodegrading inosine and guanosine using B. paranthracis YD01.

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Design, synthesis, and biological studies of dual URAT1 inhibitor and FXR agonist based on benzbromarone

Cited by 3 publications

References 24 publications

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Discovery of a Potent and Orally Bioavailable Xanthine Oxidase/Urate Transporter 1 Dual Inhibitor as a Potential Treatment for Hyperuricemia and Gout

Biodegradation of Inosine and Guanosine by Bacillus paranthracis YD01

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