- 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
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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.
- Yu, Yancheng,Yang, Fulai,Yu, Quanwei,Liu, Simeng,Wu, Chenyang,Su, Kaijun,Yang, Le,Bao, Xiaoqian,Li, Zhihong,Li, Xiang,Zhang, Xiaojin
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p. 17384 - 17402
(2021/11/16)
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- Efficient synthesis of 1,2-benzisothiazoles from: O -haloarylamidines and elemental sulfur via N-S/C-S bond formation under transition-metal-free conditions
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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.
- Xie, Hao,Li, Guozheng,Zhang, Feng,Xiao, Fuhong,Deng, Guo-Jun
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supporting information
p. 827 - 831
(2018/03/02)
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- Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity
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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.
- 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
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p. 2706 - 2711
(2008/12/20)
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