4930-03-4Relevant articles and documents
Selective JAK2 Pseudokinase Ligands and Methods of Use
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, (2022/04/16)
The compounds of Formula I described herein regulate activity of JAK2 by specifically binding to the JAK2 pseudokinase domain, JH2, and are useful as therapeutic agents in the treatment or amelioration of myeloproliferative disorders. Also provided herein are methods of treating myeloproliferative disorders, and methods of making compounds of Formula I.
Copper-Catalyzed Coupling of Amines with Carbazates: An Approach to Carbamates
Wang, Song-Ning,Zhang, Guo-Yu,Shoberu, Adedamola,Zou, Jian-Ping
, p. 9067 - 9075 (2021/07/19)
A new approach for the preparation of carbamatesviathe copper-catalyzed cross-coupling reaction of amines with alkoxycarbonyl radicals generated from carbazates is described. This environmentally friendly protocol takes place under mild conditions and is compatible with a wide range of amines, including aromatic/aliphatic and primary/secondary substrates.
Interrupted aza-Wittig reactions using iminophosphoranes to synthesize 11C-carbonyls
Ismailani, Uzair S.,Munch, Maxime,Mair, Braeden A.,Rotstein, Benjamin H.
supporting information, p. 5266 - 5269 (2021/06/06)
A direct CO2-fixation methodology couples structurally diverse iminophosphoranes with various nucleophiles to synthesize ureas, carbamates, thiocarbamates, and amides, and is amenable for 11C radiolabeling. This methodology is practical, as demonstrated by the synthesis of >35 products and isolation of the molecular imaging radiopharmaceuticals [11C]URB694 and [11C]glibenclamide. This journal is
Ligand-based optimization to identify novel 2-aminobenzo[d]thiazole derivatives as potent sEH inhibitors with anti-inflammatory effects
Han, Yufei,Huang, Desheng,Xu, Sicong,Li, Lingling,Tian, Ye,Li, Shuo,Chen, Cong,Li, Yingxiu,Sun, Yanping,Hou, Yunlei,Sun, Yongjun,Qin, Mingze,Gong, Ping,Gao, Zibin,Zhao, Yanfang
, (2020/12/07)
Inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapeutic approach in the treatment of inflammation. Driven by the in-house database product lead 1, a hybridization strategy was utilized for the design of a series of novel benzo [d]thiazol derivatives. To our delight, D016, a byproduct of compound 9, was obtained with an extraordinarily low IC50 value of 0.1 nM but poor physical and chemical properties. After removal of a non-essential urea moiety or replacement of the urea group by an amide group, compounds 15a, 17p, and 18d were identified as promising sEH inhibitors, and their molecular binding modes to sEH were constructed. Furthermore, compounds 15a and 18d exhibited more effective in vivo anti-inflammatory effect than t-AUCB in carrageenan-induced mouse paw edema. Compound 15a also showed moderate metabolic stability with a half-time of 34.7 min. Although 18d was unstable in rat liver microsomes, it might be a “prodrug”. In conclusion, this study could provide valuable insights into discovery of new sEH inhibitors, and compounds 15a and 18d were worthy of further development as potential drug candidates to treat inflammation.
Design, synthesis, and biological activity of novel semicarbazones as potent Ryanodine receptor1 inhibitors of Alzheimer's disease
Dai, Baozhu,Ma, Xingxing,Tang, Yadong,Xu, Le,Guo, Su,Chen, Xinyan,Lu, Shitong,Wang, Guangjie,Liu, Yajing
, (2020/12/09)
Ryanodine receptors (RyRs) are important ligand-gated Ca2+ channels; their excessive activation leads to Ca2+ leakage in the sarcoplasmic reticulum that may cause neurological diseases. In this study, three series of novel potent RyR1 inhibitors based on dantrolene and bearing semicarbazone and imidazolyl moieties were designed and synthesized, and their biological activity was evaluated. Using a single-cell calcium imaging method, the calcium overload inhibitory activities of 26 target compounds were tested in the R614C cell line, using dantrolene as a positive control. The preliminary investigation showed that compound 12a suppressed Ca2+ release as evidenced by store overload-induced Ca2+release (SOICR) (31.5 ± 0.1%, 77.2 ± 0.1%, 93.7 ± 0.2%) at 0.1 μM, 3 μM and 10 μM, respectively. Docking simulation results showed that compound 12a could bind at the active site of the RyR1 protein. The Morris water-maze test showed that compound 12a significantly improved the cognitive behavior of AD-model mice. Further studies on the structural optimization of this series of derivatives are currently underway in our laboratory.
AMPK agonist compound or pharmaceutically acceptable salt or ester or solvate thereof and application thereof
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Paragraph 0125-0128, (2021/07/17)
The invention discloses an AMPK agonist compound with structures shown as I and II or pharmaceutically acceptable salt or ester or solvate thereof and application thereof. Benzyloxy aryl amide and piperidine urea compounds have strong AMPK agonist activit
Selective Janus Kinase 2 (JAK2) Pseudokinase Ligands with a Diaminotriazole Core
Liosi, Maria-Elena,Krimmer, Stefan G.,Newton, Ana S.,Dawson, Thomas K.,Puleo, David E.,Cutrona, Kara J.,Suzuki, Yoshihisa,Schlessinger, Joseph,Jorgensen, William L.
, p. 5324 - 5340 (2020/06/10)
Janus kinases (JAKs) are non-receptor tyrosine kinases that are essential components of the JAK-STAT signaling pathway. Associated aberrant signaling is responsible for many forms of cancer and disorders of the immune system. The present focus is on the d
Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)-N-phenylpiperidine-1-carboxamide as novel potent analgesic
Fu, Wei,Huang, Huoming,Li, Wei,Liu, Jinggen,Wang, Wenli,Wang, Yujun,Xu, Xuejun,Zhu, Chen
, (2020/01/28)
Management of moderate to severe pain by clinically used opioid analgesics is associated with a plethora of side effects. Despite many efforts have been dedicated to reduce undesirable side effects, moderate progress has been made. In this work, starting from Tramadol, a series of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxamide derivatives were designed and synthesized, and their in vitro and in vivo activities were evaluated. Our campaign afforded selective μ opioid receptor (MOR) ligand 2a (KiMOR: 7.3 ± 0.5 nM; KiDOR: 849.4 ± 96.6 nM; KiKOR: 49.1 ± 6.9 nM) as potent analgesic with ED50 of 3.1 mg/kg in 55 °C hot plate model. Its antinociception effect was blocked by opioid antagonist naloxone. High binding affinity toward MOR of compound 2a was associated with water bridge, salt bridge, hydrogen bond and hydrophobic interaction with MOR. The high selectivity of compound 2a for MOR over δ opioid receptor (DOR) and κ opioid receptor (KOR) was due to steric hindrance of compound 2a with DOR and KOR. 2a, a compound with novel scaffold, could serve as a lead for the development of novel opioid ligands.
Discovery of AdipoRon analogues as novel AMPK activators without inhibiting mitochondrial complex I
Chen, Caiping,Cheng, Keguang,Cheng, Yalong,Dai, Liang,Li, Haobin,Qian, Ming,Sun, Geng,Wang, Pengfei,Wen, Xiaoan,Xu, Qing-Long,You, Yanping,Yuan, Haoliang,Zhou, Xinyu
supporting information, (2020/06/08)
Activation of AMPK emerges as a potential therapeutic approach to metabolic diseases. AdipoRon is claimed to be an adiponectin receptor agonist that activates AMPK through adiponectin receptor 1 (AdipoR1). However, AdipoRon also exhibits moderate inhibition of mitochondrial complex I, leading to increased risk of lactic acidosis. In order to find novel AdipoRon analogues that activate AMPK without inhibition of complex I, 27 analogues of AdipoRon were designed, synthesized and biologically evaluated. As results, benzyloxy arylamide B10 was identified as a potent AMPK activator without inhibition of complex I. B10 dose-dependently improved glucose tolerance in normal mice, and significantly lowered fasting blood glucose level and ameliorated insulin resistance in db/db diabetic mice. More importantly, unlike the pan-AMPK activator MK-8722, B10 did not cause cardiac hypertrophy, probably owing to its selective activation of AMPK in the muscle tissue but not in the heart tissue. Together, B10 represents a novel class of AMPK activators with promising therapeutic potential against metabolic disease.
A Fe3O4?SiO2/Schiff Base/Pd Complex as an Efficient Heterogeneous and Recyclable Nanocatalyst for One-Pot Domino Synthesis of Carbamates and Unsymmetrical Ureas
Inaloo, Iman Dindarloo,Majnooni, Sahar
, p. 6359 - 6368 (2019/11/05)
A palladium-catalyzed domino method for the direct synthesis of carbamates and ureas has been developed by using readily available and economical starting materials (aryl halide, carbon monoxide, sodium azide, amines and alcohols) in a one-pot approach. The domino process underwent carbonylation, Curtius rearrangement, and nucleophilic addition. This protocol provides a step-economical and highly efficient reaction to access the wide range of valuable carbamates, symmetrical and unsymmetrical ureas with high yields under remarkable mild reaction conditions that are important factors in pharmaceutical science, biochemistry and agricultural industries. Furthermore, the magnetically recoverable nanocatalyst (Fe3O4?SiO2/Pd(II)) can be conveniently and swiftly recycled using external magnet and reused at least for seven times without noticeable loss of its catalytic activity.
