- Microwave-assisted organic acid-base-co-catalyzed tandem Meinwald rearrangement and annulation of styrylepoxides
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A novel organic acid-base-co-catalyzed conversion of styrylepoxides into [1,1′-biaryl]-3-carbaldehydes was realized under microwave irradiation. Styrylepoxides first underwent an acid-catalyzed Meinwald rearrangement followed by a tandem base-catalyzed Michael addition, aldol addition, and aromatization sequence to generate [1,1′-biaryl]-3-carbaldehydes.
- Shi, Yi,Li, Siqi,Lu, Yang,Zhao, Zizhen,Li, Pingfan,Xu, Jiaxi
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supporting information
p. 2131 - 2134
(2020/02/27)
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- Design, synthesis and biological evaluation of novel FFA1/GPR40 agonists: New breakthrough in an old scaffold
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Based on an old phenoxyacetic acid scaffold, CPU014 (compound 14) has been identified as a superior agonist by comprehensive exploration of structure-activity relationship. In vitro toxicity study suggested that CPU014 has lower risk of hepatotoxicity than TAK-875. During acute toxicity study (5–500 mg/kg), a favorable therapeutic window of CPU014 was observed by evaluation of plasma profiles and liver slices. Moreover, CPU014 promotes insulin secretion in a glucose-dependent manner, while no GLP-1 secretion has been enhanced. Other than good pharmacokinetic properties, CPU014 significantly improved glucose tolerance both in normal and diabetic models without the risk of hypoglycemia. These subversive findings provided a safer candidate CPU014, which is currently in preclinical study to assess its potential for the treatment of diabetes.
- Li,Liu, Chunxia,Yang, Jianyong,Zhou,Ye, Zhiwen,Feng,Yue, Na,Tong,Huang, Wenlong,Qian, Hai
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p. 608 - 622
(2019/07/05)
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- Discovery of phenylsulfonyl acetic acid derivatives with improved efficacy and safety as potent free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
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The free fatty acid receptor 1 (FFA1) has emerged as an attractive anti-diabetic target that mediates glucose-stimulated insulin secretion. Several FFA1 agonists have been reported, but many of them possessed somewhat high lipophilicity and/or molecular weight. Herein, we describe the identification of sulfone-carboxylic acid moiety with the multiple advantages of reducing lipophilicity, cytotoxicity and β-oxidation associated with compound 2. Further structure-activity relationship study based on the previleged scaffolds led to the discovery of 2-{(4-[(2’-chloro-[1,1’-biphenyl]-3-yl)methoxy]phenyl)sulfonyl}acetic acid (compound 20), which showed a better balance than compound 2 in terms of physicochemical properties, cytotoxicity profiles and pharmacokinetic properties. Subsequent in vivo studies demonstrated that compound 20 robustly improves the glucose tolerance both in normal and type 2 diabetic models without the risk of hypoglycemia. Compared to the high risk of TAK-875 induced liver toxicity, there was no significant adverse effects such as hepatic and renal toxicity were observed in the chronic toxicity studies of compound 20 even at the higher dose.
- Li, Zheng,Liu, Chunxia,Xu, Xue,Qiu, Qianqian,Su, Xin,Dai, Yuxuan,Yang, Jianyong,Li, Huilan,Shi, Wei,Liao, Chen,Pan, Miaobo,Huang, Wenlong,Qian, Hai
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p. 458 - 479
(2017/07/10)
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- Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists
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The 5-HT7 receptor (5-HT7R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5- HT7R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT
- Kim, Jeeyeon,Kim, Youngjae,Tae, Jinsung,Yeom, Miyoung,Moon, Bongjin,Huang, Xi-Ping,Roth, Bryan L.,Lee, Kangho,Rhim, Hyewhon,Choo,Chong, Youhoon,Keum, Gyochang,Nam, Ghilsoo,Choo, Hyunah
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p. 1855 - 1864
(2014/01/06)
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