1025692-47-0Relevant academic research and scientific papers
Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design
Dong, Xiaowu,Zhan, Wenhu,Zhao, Mengting,Che, Jinxin,Dai, Xiaoyang,Wu, Yizhe,Xu, Lei,Zhou, Yubo,Zhao, Yanmei,Tian, Tian,Cheng, Gang,Jin, Zegao,Li, Jia,Shao, Yanfei,He, Qiaojun,Yang, Bo,Weng, Qinjie,Hu, Yongzhou
supporting information, p. 7264 - 7288 (2019/08/20)
A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, A12, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure-activity relationship of compound A12, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.
Synthesis and biological evaluation of novel inhibitors against 1,3,8-trihydroxynaphthalene reductase from Magnaporthe grisea
Chen, Haifeng,Han, Xinya,Qin, Nian,Wei, Lin,Yang, Yue,Rao, Li,Chi, Bo,Feng, Lingling,Ren, Yanliang,Wan, Jian
, p. 1225 - 1230 (2016/03/01)
1,3,8-Trihydroxynaphthalene reductase (3HNR) is an essential enzymes that is involved in fungal melanin biosynthesis. Based on the structural informations of active site of 3HNR, a series of β-nitrostyrene compounds were rationally designed and synthesized. The enzymatic activities of these compounds showed that most of them exhibited high inhibitory activities (50 = 0.29 μM). In particular, some of these compounds had moderate fungicidal activity against Magnaporthe grisea. Compound 3-4 showed high in vivo activities against M. grisea (EC50 = 9.5 ppm). Furthermore, compound 3-2 was selected as a representative molecule, and the probable binding mode of this compound and the surrounding residues in the active site of 3HNR was elucidated by using molecular dock. The positive results suggest that β-nitrostyrene derivatives are most likely to be promising leads toward the discovery of novel agent of rice blast.
17a-HYDROXYLASE/C17,20-LYASE INHIBITORS
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Paragraph 0812, (2014/03/21)
The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
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Page/Page column 126, (2012/04/04)
The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
A COMBINATION OF NIACIN AND A PROSTAGLANDIN D2 RECEPTOR ANTAGONIST
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Page/Page column 191, (2008/06/13)
The present invention is directed to a pharmaceutical composition comprising Niacin or a pharmaceutically acceptable salt, solvate or N-oxide thereof, or a nicotinic acid receptor agonist, and a compound of formula (I) as defined herein, or an N-oxide thereof, or an ester prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and its use for treating atherosclerosis, dyslipidemia, diabetes or a related condition while reducing substantial flushing.
Potent and selective non-benzodioxole-containing endothelin-A receptor antagonists
Tasker, Andrew S.,Sorensen, Bryan K.,Jae, Hwan-Soo,Winn, Martin,Von Geldern, Thomas W.,Dixon, Douglas B.,Chiou, William J.,Dayton, Brian D.,Calzadila, Samuel,Hernandez, Lisa,Marsh, Kennan C.,WuWong, J. Ruth,Opgenorth, Terry J.
, p. 322 - 330 (2007/10/03)
The benzodioxole ((methylenedioxy)benzene) group is present in a number of endothelin (ET) receptor antagonists thus far reported. As part of our own endothelin antagonist program we have developed (2R*,3R*,4S*)-1-(N,N- dibutylacetamido)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)pyrrolidine-3- carboxylic acid (A-127722). This is a potent antagonist, binding to the ET(A) and ET(B) receptor subtypes with affinities (IC50) of 0.4 and 520 nM, respectively, and also contains the aforementioned benzodioxole. While this compound was seemingly optimized at its N-terminus, no effort had been directed toward understanding the contributions to binding affinity or receptor subtype selectivity conferred by the benzodioxole. Substitution by 1- or 2-naphthyl yielded weak antagonists. Oxygenated benzenes, such as p- anisyl, were potent compounds with IC50s in the low-nanomolar range. Simple deletion of either of the two oxygen atoms (dihydrobenzofurans) yielded extremely potent agents, possessing subnanomolar affinity for the ET(A) receptor. Additionally, the compounds showed enhanced selectivity, binding to the ET(B) receptor subtype in the micromolar range. This paper describes the development of this novel class of compounds.
