13916-99-9Relevant academic research and scientific papers
Nickel-Catalyzed Cyanation of Aryl Halides and Hydrocyanation of Alkynes via C-CN Bond Cleavage and Cyano Transfer
Chen, Hui,Sun, Shuhao,Liu, Yahu A.,Liao, Xuebin
, p. 1397 - 1405 (2020/02/04)
We report nickel-catalyzed cyanation and hydrocyanation methods to prepare aryl nitriles and vinyl nitriles from aryl halides and alkynes, respectively. Using inexpensive and nontoxic 4-cyanopyridine N-oxide as the cyano shuttle, the methods provide an efficient approach to prepare aryl cyanides and vinyl nitriles under mild and operationally simple reaction conditions with a broad range of functional group tolerances. In hydrocyanation of alkynes, the method demonstrated good regioselectivity, producing predominantly E- or Z-alkenyl nitriles in a controlled manner and exclusively Markovnikov vinyl nitriles when internal diaryl alkynes and terminal alkynes were applied as the substrates, respectively. The preliminary mechanistic investigation indicated that the C-CN bond cleavage process is promoted by oxidative addition to the nickel(I) complex in the cyanation of aryl halides, and further studies via a series of deuterium exchange experiments indicated that water serves as the hydrogen source for the hydrocyanation of alkynes.
Discovery of flexible naphthyltriazolylmethane-based thioacetic acids as highly active uric acid transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia of gout
Zhang, Xiansheng,Wu, Jingwei,Liu, Wei,Liu, Yuqiang,Xie, Yafei,Shang, Qian,Zhou, Zhixing,Xu, Weiren,Tang, Lida,Wang, Jianwu,Zhao, Guilong
, p. 260 - 281 (2017/05/31)
Background: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. Objective: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor. Methods: The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1. Results: Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 μM and 0.094 μM, respectively, against human URAT1 vs 7.18 μM for lesinurad). Conclusion: Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane-bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton.
Design, synthesis and biological evaluation of aminobenzyloxyarylamide derivatives as selective κ opioid receptor antagonists
Wang, Junwei,Song, Qiao,Xu, Anhua,Bao, Yu,Xu, Yungen,Zhu, Qihua
, p. 15 - 25 (2017/03/02)
Opioid receptors play an important role in both behavioral and mood functions. Based on the structural modification of LY2456302, a series of aminobenzyloxyarylamide derivatives were designed and synthesized as κ opioid receptor antagonists. The κ opioid receptor binding ability of these compounds were evaluated with opioid receptors binding assays. Compounds 1a-d showed high affinity for κ opioid receptor. Especially for compound 1c, exhibited a significant Kivalue of 15.7?nM for κ opioid receptor binding and a higher selectivity over μ and δ opioid receptors compared to (±)LY2456302. In addition, compound 1c also showed potent κ antagonist activity with κ IC50?=?9.32?nM in [35S]GTP-γ-S functional assay. The potential use of the representative compounds as antidepressants was also investigated. The most potent compound 1c not only exhibited potent antidepressant activity in the mice forced swimming test, but also displayed the effect of anti-anxiety in the elevated plus-maze test.
