134446-36-9Relevant academic research and scientific papers
Exploring Halogen Bonds in 5-Hydroxytryptamine 2B Receptor-Ligand Interactions
Zhou, Yu,Wang, Yuanxun,Li, Pengfei,Huang, Xi-Ping,Qi, Xiangbin,Du, Yunfei,Huang, Niu
, p. 1019 - 1024 (2018)
Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to further explore the opportunity of "designing in" halogen bonding interactions in structure-based ligand design for the 5-HT2B receptor, which not only facilitated the identification of previously uncharacterized halogen bonds in known 5-HT2B ligands but also enabled the rational design of halogen bonding interactions for the optimization of 5-HT2B ligands. As a proof-of-concept, a series of halogen-substituted analogues of doxepin was synthesized and evaluated, which showed improved in vitro and in vivo potency.
MONO HALOGEN OR METHYL-SUBSTITUTED 5-HT2B ANTAGONISTS WITH INCREASED ACTIVITY
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Paragraph 0050; 0064, (2020/05/13)
Disclose herein are mono halogen or methyl-substituted 5-HT 2B antagonist compounds, which have been found with increased binding activity to 5-HT 2B receptor due to the substitution of halogen or methyl, and the method of using the compounds of treating or preventing a disorder mediated by 5-HT 2B.
Development of Dihydrodibenzooxepine Peroxisome Proliferator-Activated Receptor (PPAR) Gamma Ligands of a Novel Binding Mode as Anticancer Agents: Effective Mimicry of Chiral Structures by Olefinic E/Z-Isomers
Yamamoto, Keisuke,Tamura, Tomohiro,Henmi, Kazuki,Kuboyama, Takeshi,Yanagisawa, Arata,Matsubara, Masahiro,Takahashi, Yuichi,Suzuki, Michihiko,Saito, Jun-Ichi,Ueno, Kimihisa,Shuto, Satoshi
supporting information, p. 10067 - 10083 (2018/11/23)
A novel class of PPARγ ligand 1 (EC50 = 197 nM) with a dibenzoazepin scaffold was identified through high-throughput screening campaign. To avoid the synthetically troublesome chiral center of 1, its conformational analysis using the MacroModel was conducted, focusing on conformational flip of the tricyclic ring and the conformational restriction by the methyl group at the chiral center. On the basis of this analysis, scaffold hopping of dibenzoazepine into dibenzo[b,e]oxepine by replacing the chiral structures with the corresponding olefinic E/Z isomers was performed. Consequently, dibenzo[b,e]oxepine scaffold 9 was developed showing extremely potent PPARγ reporter activity (EC50 = 2.4 nM, efficacy = 9.5%) as well as differentiation-inducing activity against a gastric cancer cell line MKN-45 that was more potent than any other well-known PPARγ agonists in vitro (94% at 30 nM). The X-ray crystal structure analysis of 9 complexed with PPARγ showed that it had a unique binding mode to PPARγ ligand-binding domain that differed from that of any other PPARγ agonists identified thus far.
