400898-92-2Relevant academic research and scientific papers
Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives
Fukuda, Takeshi,Ishiyama, Takashi,Katagiri, Takahiro,Ueda, Kenjiro,Muramatsu, Sumie,Hashimoto, Masami,Aki, Anri,Baba, Daichi,Watanabe, Kengo,Tanaka, Naoki
, p. 3333 - 3337 (2018)
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure–activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.
Discovery of Hydroxyamidine Derivatives as Highly Potent, Selective Indoleamine-2,3-dioxygenase 1 Inhibitors
Jin, Fangfang,Hu, Qiyue,Fei, Hongbo,Lv, Hejun,Wang, Shenglan,Gui, Bin,Zhang, Junzhen,Tu, Wangyang,Zhang, Yun,Zhang, Lei,Wan, Hong,Zhang, Limin,Hu, Bin,Yang, Fanglong,Bai, Chang,He, Feng,Zhang, Lianshan,Tao, Weikang
, p. 195 - 201 (2021/02/06)
In this study, a series of novel hydroxyamidine derivatives were identified as potent and selective IDO1 inhibitors by structure-based drug design. Among them, compounds 13-15 and 18 exhibited favorable enzymatic and cellular activities. Compound 18 showed improved bioavailability in mouse, rat, and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable in vivo pharmacokinetic properties, compound 18 was further evaluated in a transgenic MC38 xenograft mouse model. The combination of compound 18 with PD-1 monoclonal antibody showed a synergistic antitumor effect. These data indicated that compound 18 as a potential cancer immunotherapy agent should warrant further investigation.
Cytotoxic effects of combination of oxidosqualene cyclase inhibitors with atorvastatin in human cancer cells
Staedler, Davide,Chapuis-Bernasconi, Catherine,Dehmlow, Henrietta,Fischer, Holger,Juillerat-Jeanneret, Lucienne,Aebi, Johannes D.
supporting information; experimental part, p. 4990 - 5002 (2012/08/28)
Ten oxidosqualene cyclase inhibitors with high efficacy as cholesterol-lowering agents and of different chemical structure classes were evaluated as potential anticancer agents against human cancer cells from various tissue origins and nontumoral human-brain-derived endothelial cells. Inhibition of cancer cell growth was demonstrated at micromolar concentrations, comparable to the concentrations of statins necessary for antitumor effect. Human glioblastoma cells were among the most sensitive cells. These compounds were also able to decrease the proliferation of angiogenic brain-derived endothelial cells, as a model of tumor-induced neovasculation. Additive effects in human glioblastoma cells were also demonstrated for oxidosqualene cyclase inhibitors in combination with atorvastatin while maintaining selectivity against endothelial cells. Thus, not only statins targeting the 3-hydroxy-3- methylglutaryl coenzyme A reductase but also inhibitors of oxidosqualene cyclase decrease tumor growth, suggesting new therapeutic opportunities of combined anti-cholesterol agents for dual treatment of glioblastoma.
