1145-58-0Relevant articles and documents
Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture
Kühl, Nikos,Leuthold, Mila M.,Behnam, Mira A. M.,Klein, Christian D.
, p. 4567 - 4587 (2021/05/06)
The viral serine protease NS2B-NS3 is one of the promising targets for drug discovery against dengue virus and other flaviviruses. The molecular recognition preferences of the protease favor basic, positively charged moieties as substrates and inhibitors, which leads to pharmacokinetic liabilities and off-target interactions with host proteases such as thrombin. We here present the results of efforts that were aimed specifically at the discovery and development of noncharged, small-molecular inhibitors of the flaviviral proteases. A key factor in the discovery of these compounds was a cellular reporter gene assay for the dengue protease, the DENV2proHeLa system. Extensive structure-activity relationship explorations resulted in novel benzamide derivatives with submicromolar activities in viral replication assays (EC50 0.24 μM), selectivity against off-target proteases, and negligible cytotoxicity. This structural class has increased drug-likeness compared to most of the previously published active-site-directed flaviviral protease inhibitors and includes promising candidates for further preclinical development.
Synthesis and structure–activity relationship of N-(piperidin-4-yl)benzamide derivatives as activators of hypoxia-inducible factor 1 pathways
Huang, Zhi-Ning,Liang, Han,Qiao, Hong,Wang, Bao-Rui,Qu, Ning,Li, Hua,Zhou, Run-Run,Wang, Li-Juan,Li, Shan-Hua,Li, Fu-Nan
, p. 1149 - 1161 (2018/07/21)
Guided by bioisosterism and pharmacokinetic parameters, we designed and synthesized a series of novel benzamide derivatives. Preliminary in vitro studies indicated that compounds 10b and 10j show significant inhibitory bioactivity in HepG2 cells (IC50 values of 0.12 and 0.13?μM, respectively). Compounds 10b and 10j induced the expression of HIF-1α protein and downstream target gene p21, and upregulated the expression of cleaved caspase-3 to promote tumor cells apoptosis.
Identification of highly potent N-acylethanolamine acid amidase (NAAA) inhibitors: Optimization of the terminal phenyl moiety of oxazolidone derivatives
Li, Yuhang,Chen, Qi,Yang, Longhe,Li, Yanting,Zhang, Yang,Qiu, Yan,Ren, Jie,Lu, Canzhong
, p. 214 - 221 (2017/08/16)
N-acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that participates in the deactivation of fatty acid ethanolamides, such as palmitoylethanolamide (PEA). NAAA inhibition may provide a potential therapeutic strategy for the treatment of diseases in which higher PEA level is desired. In the present study, we reported the structure-activity relationship (SAR) studies for oxazolidone derivatives as NAAA inhibitors. A series of substituents or alkyl replacements for the terminal phenyl ring of oxazolidone derivatives were examined. The results showed that the inhibition potency of these oxazolidone derivatives towards NAAA depends on the sizes, flexibility, and lipophilicity of the terminal groups. SAR results suggested that small lipophilic 3-phenyl substituents or hydroxy-containing 4-phenyl substituents were preferable for optimal potency. Furthermore, the distal aliphatic replacement is also preferred for high inhibitory potency. Rapid dilution and kinetic analysis suggested that oxazolidone derivatives with different terminal phenyl moieties inhibited NAAA via different mechanisms. This study identified several highly potent NAAA inhibitors, including 1a (F215, IC50 = 0.009 μM), 1o (IC50 = 0.061 μM) and 2e (IC50 = 0.092 μM), and also determined structural requirements of oxazolidone derivatives for potent inhibition against NAAA.
1-substituted 4-arylpiperazine as kappa opioid receptor antagonists
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Page/Page column 26, (2016/12/26)
Provided are compounds represented by the formula: where R, Y3, R1, R2, R3, R4, R6, G, R7, E1, E2, A, B, W, X, Y and Z are as defined herein.
1-SUBSTITUTED 4-ARYLPIPERAZINE AS KAPPA OPIOID RECEPTOR ANTAGONISTS
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Page/Page column 33, (2013/06/27)
Provided are compounds represented by the formula: where R, Y3, R1,R2, R3, R4, R6, G, R7, E1, E2, A, B, W, X, Y and Z are as defined herein.
Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2- methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists
Kormos, Chad M.,Jin, Chunyang,Cueva, Juan Pablo,Runyon, Scott P.,Thomas, James B.,Brieaddy, Lawrence E.,Mascarella, S. Wayne,Navarro, Hernán A.,Gilmour, Brian P.,Carroll, F. Ivy
, p. 4551 - 4567 (2013/07/19)
There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study, we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [35S] GTPγS binding assay showed that neither compound showed the high potency and κ opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [35S]GTPγS binding stimulated by the selective κ opioid agonist U69,593. These studies led to N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3- methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide (11a), a compound that showed good κ opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [35S]GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists.
