Design, synthesis and biological activity of tetrazole-bearing uric acid transporter 1 inhibitors

Cai, Wenqing; Liu, Wei; Xie, Yizhen; Wu, Jingwei; Liu, Yuqiang; Liu, Changying; Xu, Weifeng; Li-da, Tang; Wang, Jianwu; Zhao, Guilong

doi:10.1007/s40242-017-6351-3

Cited by 8 publications

(2 citation statements)

References 20 publications

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“…Recently, considerable attention has been paid to the burden of gout on the individual and community as well as the discovery of URAT1 inhibitors on identification of URAT1 as a druggable therapeutic target, with lesinurad being approved and a number of others under development in clinical trials ( Figure 1 ) [ 24 , 25 , 26 , 27 , 28 , 29 ]. In the effort to discover potent URAT1 inhibitors based on the structure of lesinurad in our laboratories, earlier studies successfully delivered a number of highly potent URAT1 inhibitors, and the IC 50 values of some of them are even lower by almost two orders of magnitude than lesinurad ( Figure 2 ) [ 30 , 31 , 32 , 33 , 34 ]. These highly potent URAT1 inhibitors share a common structural feature, i.e., a carboxylic group (in blue) connected to a flexible naphthyltriazolylmethane backbone (in red) by a linker.…”

Section: Introductionmentioning

confidence: 99%

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

Cai

Liu

et al. 2018

Molecules

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In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a–1x and 1ha–1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.

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Section: Introductionmentioning

confidence: 99%

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

Cai

Liu

et al. 2018

Molecules

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“…对于醇钠的产生方法, 我们试验了 NaH/ EtOH/THF [13] 和 EtONa/EtOH 两个体系, 前者是在 THF 中 NaH 与 EtOH 反应制备 EtONa, 后者是将金属钠溶于无水 EtOH 中制得 EtONa, 过量的 EtOH 作反应溶剂; 我们也尝试了使用 CuCl 作为催化剂 [14] 来考察是否会提高 S N Ar 的收率. 从表 2 可以看出, 使用 NaH 与 EtOH 反应 [18] . 12 先与酰肼 7 反应, 得到的加成产物经过 NaOH 处理关环 , 得到三唑硫酮 13 [19,20] [24] : 88 ～90 ℃ ); 1…”

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Efficient Synthetic Approaches to Uric Acid Transporter 1 Inhibitors Bearing Alkoxyl Group-Substituted Triazoles

Tian¹,

Liu²,

Xie³

et al. 2017

Chin. J. Org. Chem.

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Uric acid transporter 1 (URAT1) inhibitors bearing alkoxy group-substituted triazoles 3-(4-(4-cyclopropylnaphthalen-1-yl)-5-methoxy-4H-1,2,4-triazol-3-yl)propanoic acid (1a) and 3-(4-(4-cyclopropylnaphthalen-1-yl)-5-ethoxy-4H-1,2,4-triazol-3-yl)propanoic acid (1b) are structurally interesting lead compounds in drug design. The current synthetic approach to them suffers from quite low overall yields (3.3% and 3.0% for 1a and 1b, respectively). In order to explore the structure-activity relationship (SAR) of 1a and 1b, synthetic approach with higher overall yield is urgently needed. In the present study, two efficient synthetic approaches to 1a and 1b were developed (approaches A and B), with CuCl-catalyzed nucleophilic aromatic substitution (S N Ar) reaction of bromotriazole with sodium alkoxides and S N Ar reaction of methylsulfonyltriazole with sodium alkoxides as key steps, and the conditions for important steps were fully optimized. The two synthetic approaches are characterized by dramatically higher yields, and not only valuable to the further SAR exploration of 1a and 1b but also very helpful to the synthesis of heterocycles with alkoxyl groups.

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A facile synthetic approach to 3-halo-4-substituted-1,5-dihydro-4H-1,2,4-triazoline-5-thiones based on retro-Michael addition

Tian

Liu

et al. 2017

Chem. Res. Chin. Univ.

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Design, synthesis and biological activity of tetrazole-bearing uric acid transporter 1 inhibitors

Cited by 8 publications

References 20 publications

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

Efficient Synthetic Approaches to Uric Acid Transporter 1 Inhibitors Bearing Alkoxyl Group-Substituted Triazoles

A facile synthetic approach to 3-halo-4-substituted-1,5-dihydro-4H-1,2,4-triazoline-5-thiones based on retro-Michael addition

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