- Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment
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Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (D2Rs) are the main target in the treatment of schizophrenia, in particular for mitigation of the positive symptoms. Due to the high expression of 5-hydroxytryptamine type 3 receptors (5-HT3Rs) in human brain areas responsible for emotional behavior, motivation, and cognitive function, 5-HT3Rs represent a potential target for modulating the cognitive and negative symptoms of schizophrenia. Here we present the design, synthesis, and both in vitro and in vivo biological evaluation of 1,4-disubstituted aromatic piperazines. Screening of in vitro properties revealed the two most promising drug candidates (21 and 24) which were found to be potent D2Rs and moderate 5-HT3R antagonists, and which were forwarded to in vivo studies in Wistar rats. Considering toxicity, administration of the maximal feasible dose of 21 (2 mg/kg) did not produce any side effects. By contrast, the higher solubility of 24 led to revelation of mild and temporary side effects at the dose of 20 mg/kg. Importantly, both 21 and 24 showed facile crossing of the blood-brain barrier, even exerting higher levels in the brain in comparison to plasma. In a behavioral study using the acute amphetamine model of psychosis, we showed that compound 24 ameliorated both positive and negative effects of amphetamine including hyperlocomotion, social impairments, and disruption of prepulse inhibition. The effect of the highest dose (10 mg/kg) was comparable to the effect of the reference dose of aripiprazole (1 mg/kg).
- Bojarski, Andrzej J.,Dehaen, Wim,Janousek, Jiri,Juza, Radomir,Karasova, Jana Zdarova,Kobrlova, Tereza,Korabecny, Jan,Kubacka, Monika,Mezeiova, Eva,Mogilski, Szczepan,Musilek, Kamil,Pejchal, Jaroslav,Petrasek, Tomas,Prchal, Lukas,Randakova, Alena,Satala, Grzegorz,Soukup, Ondrej,Stark, Holger,Stefkova-Mazochova, Kristyna,Svozil, Daniel,Vlcek, Premysl,Vojtechova, Iveta
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- Synthesis and evaluation of 2-(4-[4-acetylpiperazine-1-carbonyl] phenyl)-1H-benzo[d]imidazole-4-carboxamide derivatives as potential PARP-1 inhibitors and preliminary study on structure-activity relationship
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Although 1H-benzo[d]imidazole-4-carboxamide derivatives have been explored for a long time, the structure–activity relationship of the substituents in the hydrophobic pocket (AD binding sites) has not thoroughly discovered. Here in, a series of 2-(4-[4-acetylpiperazine-1-carbonyl]phenyl)-1H-benzo[d]imidazole-4-carboxamide derivatives have been designed, synthesized, and successful characterization as novel and effective poly ADP-ribose polymerases (PARP)-1 inhibitors to improve the structure–activity relationships about the substituents in the hydrophobic pocket. These derivatives were evaluated for their PARP-1 inhibitory activity and cellular inhibitory against BRCA-1 deficient cells (MDA-MB-436) and wild cells (MCF-7) using PARP kit assay and MTT method. The results indicated that compared with other heterocyclic compounds, furan ring-substituted derivatives 14n-14q showed better PARP-1 inhibitory activity. Among this derivatives, compound 14p displayed the strongest inhibitory effects on PARP-1 enzyme (IC50?=?0.023 μM), which was close to that of Olaparib. 14p (IC50?=?43.56 ± 0.69 μM) and 14q (IC50?=?36.69 ± 0.83 μM) displayed good antiproliferation activity on MDA-MB-436 cells and inactivity on MCF-7 cells, indicating that 14p and 14q have high selectivity and targeting. The molecular docking method was used to explore the binding mode of compound 14p and PARP-1, and implied that the formation of hydrogen bond was essential for PARP-1 inhibition activities. This study also showed that in the hydrophobic pocket (AD binding sites), the introduction of strong electronegative groups (furan ring, e.g.) or halogen atoms in the side chain of benzimidazole might improve its inhibitory activity and this strategy could be applied in further research.
- Chen, Miaojia,Huang, Honglin,Wu, Kaiyue,Liu, Yunfan,Jiang, Lizhi,Li, Yang,Tang, Guotao,Peng, Junmei,Cao, Xuan
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- Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer
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Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
- Long, Huan,Hu, Xiaolong,Wang, Baolin,Wang, Quan,Wang, Rong,Liu, Shumeng,Xiong, Fei,Jiang, Zhenzhou,Zhang, Xiao-Qi,Ye, Wen-Cai,Wang, Hao
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p. 12089 - 12108
(2021/09/06)
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- Design, synthesis, and biological evaluation of matrine derivatives possessing piperazine moiety as antitumor agents
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Using matrine (1) as the lead compound, a series of new piperazinyl matrine derivatives were designed, synthesized and evaluated for their antitumor activities in vitro and in vivo. Structure activity relationship (SAR) analysis indicated that introductio
- Xu, Yiming,Liang, Pengyun,Rashid, Haroon ur,Wu, Lichuan,Xie, Peng,Wang, Haodong,Zhang, Shuyan,Wang, Lisheng,Jiang, Jun
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p. 1618 - 1627
(2019/07/29)
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- Structure-Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
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Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been associated with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, we present a series of targeted covalent inhibitors (TCIs) based on our previously reported Cbz-Lys scaffold. From this structure-activity relationship (SAR) study, novel irreversible inhibitors were identified that block the transamidation activity of hTG2 and allosterically abolish its GTP binding ability with a high degree of selectivity and efficiency (kinact/KI > 105 M-1 min-1). One optimized inhibitor (VA4) was also shown to inhibit epidermal cancer stem cell invasion with an EC50 of 3.9 μM, representing a significant improvement over our previously reported "hit" NC9.
- Akbar, Abdullah,McNeil, Nicole M. R.,Albert, Marie R.,Ta, Viviane,Adhikary, Gautam,Bourgeois, Karine,Eckert, Richard L.,Keillor, Jeffrey W.
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p. 7910 - 7927
(2017/10/06)
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- Kinetic study on aminolysis of y-substituted-phenyl picolinates: Effect of h-bonding interaction on reactivity and transition-state structure
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A kinetic study is reported on nucleophilic substitution reactions of Y-substituted-phenyl picolinates (7a-7h) with a series of cyclic secondary amines in 80 mol % H2O/20 mol % DMSO at 25.0 ± 0.1 °C. Comparison of the kinetic results with those reported previously for the corresponding reactions of Y-substituted-phenyl benzoates (1a-1f) reveals that 7a-7h are significantly more reactive than 1a-1f. The Bronsted-type plot for the aminolysis of 4-nitrophenyl picolinate (7a) is linear with βnuc = 0.78, which is typical for reactions proceeding through a stepwise mechanism with expulsion of the leaving group being the rate-determining step. The Bronsted-type plots for the piperidinolysis of 7a-7h and 1a-1f are also linear with βlg = -1.04 and -1.39, respectively, indicating that the more reactive 7a-7h are less selective than the less reactive 1a-1f to the leavinggroup basicity. One might suggest that the enhanced reactivity of 7a-7h is due to the inductive effect exerted by the electronegative N atom in the picolinyl moiety, while the decreased selectivity of the more reactive substrates is in accord with the reactivity-selectivity principle. However, the nature of intermediate (e.g., a stabilized cyclic intermediate through the intramolecular H-bonding interaction for the reactions of 7a-7h, which is structurally not possible for the reactions of 1a-1f) is also responsible for the enhanced reactivity with a decreased selectivity.
- Kim, Min-Young,Kang, Tae-Ah,Yoon, Jung Hwan,Um, Ik-Hwan
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p. 2410 - 2414
(2014/11/08)
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- Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)- 2H-phthalazin-1-ones as potent PARP-1 inhibitors
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We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H- phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.
- Wang, Ling-Xiao,Zhou, Xin-Bo,Xiao, Meng-Liang,Jiang, Ning,Liu, Feng,Zhou, Wen-Xia,Wang, Xiao-Kui,Zheng, Zhi-Bing,Li, Song
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p. 3739 - 3743
(2014/09/17)
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- Novel Ethanediamone Hepcidine Antagonists
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The present invention relates to novel hepcidin antagonists of formula (I), pharmaceutical compositions comprising them and the use thereof as medicaments, in particular for treatment of disorders in iron metabolism, such as, in particular, iron deficiency diseases and anaemias, in particular anaemias in connection with chronic inflammatory diseases (ACD: anaemia of chronic disease and AI: anaemia of inflammation).
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- Dipeptidyl peptidase-4 inhibitor with β-amino amide scaffold: Synthesis, SAR and biological evaluation
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Inhibitors of dipeptidyl peptidase-4 (DPP4) have been shown to be effective treatments for type 2 diabetes. Several series of β-amino amide containing piperazine derivatives have been prepared and evaluated as a inhibitor of DPP4. Finally compound 5m was selected for further evaluation.
- Kim, Heung Jae,Kwak, Woo Young,Min, Jong Pil,Sung, Si Young,Kim, Ha Dong,Kim, Mi Kyung,Kim, Hae Sun,Park, Kyung Jin,Son, Moon Ho,Kim, Soon Hoe,Lee, Bong Jin
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scheme or table
p. 5545 - 5549
(2012/09/22)
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- THIADIAZOLEDIOXIDES AND THIADIAZOLEOXIDES AS CXC- AND CC-CHEMOKINE RECEPTOR LIGANDS
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Disclosed are novel compounds of the formula (IA) and the pharmaceutically acceptable salts and solvates thereof. Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and cardiac reperfusion injury, acute pain, acute and chronic inflammatory pain, and neuropathic pain using a compound of formula (IA).
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- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
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There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
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Page 157; 158
(2008/06/13)
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- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
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There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
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Page 157-158
(2008/06/13)
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