23564-74-1Relevant articles and documents
Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia
Yu, Yancheng,Yang, Fulai,Yu, Quanwei,Liu, Simeng,Wu, Chenyang,Su, Kaijun,Yang, Le,Bao, Xiaoqian,Li, Zhihong,Li, Xiang,Zhang, Xiaojin
, p. 17384 - 17402 (2021/11/16)
Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708 mg·kg-1). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL-1) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.
Efficient synthesis of 1,2-benzisothiazoles from: O -haloarylamidines and elemental sulfur via N-S/C-S bond formation under transition-metal-free conditions
Xie, Hao,Li, Guozheng,Zhang, Feng,Xiao, Fuhong,Deng, Guo-Jun
supporting information, p. 827 - 831 (2018/03/02)
An efficient method for the synthesis of 1,2-benzisothiazoles from amidines and elemental sulfur via N-S/C-S bond formation under transition-metal-free conditions is described. This reaction is performed smoothly under simple conditions to give the corresponding products in good to high yields with good functional group tolerance.
Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity
Smith, Roger A.,Fathi, Zahra,Achebe, Furahi,Akuche, Christiana,Brown, Su-Ellen,Choi, Soongyu,Fan, Jianmei,Jenkins, Susan,Kluender, Harold C.E.,Konkar, Anish,Lavoie, Rico,Mays, Ronald,Natoli, Jennifer,O'Connor, Stephen J.,Ortiz, Astrid A.,Su, Ning,Taing, Christy,Tomlinson, Susan,Tritto, Theresa,Wang, Gan,Wirtz, Stephan-Nicholas,Wong, Wai,Yang, Xiao-Fan,Ying, Shihong,Zhang, Zhonghua
, p. 2706 - 2711 (2008/12/20)
Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 Ki = 3.7 nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.
