- Effectiveness of novel 5-(5-amino-1-aryl-1H-pyrazol-4-yl)-1H-tetrazole derivatives against promastigotes and amastigotes of leishmania amazonensis
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In this research, a series of substituted 5-(5-amino-1-aryl-1H-pyrazol-4- yl)-1H-tetrazoles were synthesized and evaluated for in vitro antileishmanial activity. Among the derivatives, examined compounds 3b and 3l exhibited promising activity against promastigotes and amastigotes forms of Leishmania amazonensis. The cytotoxicity of these compounds was evaluated on murine cells, giving access to the corresponding selectivity index (SI).
- Dos Santos Faióes, Viviane,Leon, Leonor L.,Canto-Cavalheiro, Marilene M.,Torres-Santos, Eduardo C.,Bernardino, Alice M.R.,Vegi, Percilene F.,Dos Santos, Maurício S.
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p. 272 - 277
(2014/03/21)
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- The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold
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Glucokinase is a key enzyme in glucose homeostasis since it phosphorylates glucose to give glucose-6-phosphate, which is the first step in glycolysis. GK activators have been proven to lower blood-glucose, and therefore have potential as treatments for type 2 diabetes. Here the discovery of pyrazolopyrimidine GKAs is reported. An original singleton hit from a high-throughput screen with micromolar levels of potency was optimised to give compounds with nanomolar activities. Key steps in this success were the introduction of an extra side-chain, which increased potency, and changing the linking functionality from a thioether to an ether, which led to improved potency and lipophilic ligand efficiency. This also led to more stable compounds with improved profiles in biological assays.
- Bonn, Peter,Brink, D. Mikael,F?gerhag, Jonas,Jurva, Ulrik,Robb, Graeme R.,Schnecke, Volker,Svensson Henriksson, Anette,Waring, Michael J.,Westerlund, Christer
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p. 7302 - 7305
(2013/02/23)
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- Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design
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A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC50 of 21 nM and 3.3 μM, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.
- Meng, Fei,Huang, Manna,Zhu, Xinhai,Wan, Yiqian,Hou, Jing,Shao, Yong-Xian,Cai, Yonghong,Li, Zhe,Xu, Jie,Liu, Peiqing,Luo, Hai-Bin,Ke, Hengming,Wu, Pei-Ying
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p. 8549 - 8558,10
(2020/09/15)
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- An efficient synthesis of new 5-(1-Aryl-1H-pyrazole-4-yl)-1H-tetrazoles from 1-Aryl-1H-pyrazole-4-carbonitriles via [3 + 2] cycloaddition reaction
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A series of new 5-(1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 4a-l were synthesized via [3 + 2] cycloaddition reaction from 1-aryl-1H-pyrazole-4- carbonitriles 3a-l, sodium azide and ammonium chloride, using dimethylformamide (DMF) as solvent, in good yields: 64-85%. The structures of these newly synthesized compounds were determined from the IR, 1H- and 13C-NMR spectroscopic data and elemental analyses.
- Dos Santos, Mauricio S.,Bernardino, Alice M. R.,Pinheiro, Luiz C. S.,Canto-Cavalheiro, Marilene M.,Leon, Leonor L.
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p. 1425 - 1428
(2013/02/23)
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- Discovery and evaluation of 7- lkyl-1,5-bis-aryl-pyrazolopyridinones as Highly potent, selective, and orally efficacious inhibitors of p38α mitogen-activated protein kinase
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The p38α mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1- and tumor necrosis factor α. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease, as well as other diseases where aberrant cytokine signaling is the driver of disease. In this communication, we describe a novel class of 7-alkyl-1,5-bis-aryl- pyrazolopyridinone-based p38α inhibitors. In particular, compound 3f is highly potent in the enzyme and cell-based assays, selective in an Ambit kinase screen, and efficacious (ED50 - 0.01 mg/kg) in the rat collagen induced arthritis (CIA) model.
- Pettus, Liping H.,Wurz, Ryan P.,Xu, Shimin,Herberich, Brad,Henkle, Bradley,Liu, Qiurong,McBride, Helen J.,Mu, Sharon,Plant, Matthew H.,Saris, Christiaan J.M.,Sherman, Lisa,Wong, Lu Min,Chmait, Samer,Lee, Matthew R.,Mohr, Christopher,Hsieh, Faye,Tasker, Andrew S.
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experimental part
p. 2973 - 2985
(2010/09/05)
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- Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines
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General, high-yielding MAOS protocols for the expedited synthesis of functionalized pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyrimidines, as well as their pyrazole precursors, are described amenable to an iterative analogue library synthesis strategy for lead optimization.
- Daniels, R. Nathan,Kim, Kwangho,Lebois, Evan P.,Muchalski, Hubert,Hughes, Mary,Lindsley, Craig W.
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p. 305 - 310
(2008/09/17)
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- Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators
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This letter describes the synthesis and SAR, developed through an iterative analogue library approach, of an mGluR4 positive allosteric modulator lead based on a pyrazolo[3,4-d]pyrimidine scaffold. Despite tremendous therapeutic potential, Compound 7, VU0080421, and related congeners represent only a handful of mGluR4 positive allosteric modulators ever described.
- Niswender, Colleen M.,Lebois, Evan P.,Luo, Qingwei,Kim, Kwangho,Muchalski, Hubert,Yin, Huiyong,Conn, P. Jeffrey,Lindsley, Craig W.
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experimental part
p. 5626 - 5630
(2009/07/18)
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- Aryl substituted purine analogues
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Aryl-substituted purine analogues are provided, of the formula: (I) wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treat
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Page/Page column 23
(2008/06/13)
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- 6-Arylmethyl-substituted pyrazolopyrimidines
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The invention relates to novel 6-arylmethyl-substituted pyrazolopyrimidines, process for their preparation and their use for producing medicaments for improving perception, concentration, learning and/or memory.
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- 6-ARYLMETHYL-SUBSTITUTED PYRAZOLOPYRIMIDINES
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The invention relates to novel 6-arylmethyl-substituted pyrazolopyrimidines of formula (I) wherein R1 represents phenyl, pyridyl or thiophenyl, and R2 represents phenyl or heteroaryl. The invention also relates to the salts and solvates thereof, and/or solvates of the salts thereof, to methods for producing said pyrazolopyrimidines, and to the use of the same for producing pharmaceuticals for improving perception, power of concentration, learning capacity and/or memory retention.
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Page/Page column 28-29
(2008/06/13)
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- 6-CYCLYLMETHYL- AND 6-ALKYLMETHYL-SUBSTITUTED PYRAZOLOPYRIMIDINES
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The invention relates to novel 6-cyclylmethyl- and 6-alkylmethyl-substituted pyrazolopyrimidines, method for production and use thereof for the production of medicaments for the improvement of cognition, concentration, learning and/or memory capacity.
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Page/Page column 33
(2008/06/13)
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- Synthesis and adenosine receptor affinity of a series of pyrazolo[3,4-d]pyrimidine analogues of 1-methylisoguanosine
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Pyrazolo[3,4-d]pyrimidines are pyrazolo analogues of purines. They have been shown to be a general class of compounds which exhibit A1 adenosine receptor affinity. Two series of pyrazolo[3,4-d]pyrimidine analogues of 1-methylisoguanosine have been synthesized. The first involved substitution of the N1-position while the second involved substitution of the N5-position. Both alkyl and aryl substituents were examined. All compounds were tested for A1 adenosine receptor affinity by using a (R)-[3H]-N6-(phenylisopropyl)adenosine binding assay. The 3-chlorophenyl group showed the greatest activity in the N1-position and the butyl group produced the greatest activity in the N5-position. Combination of the best substituent in each of these positions enhanced the overall activity. The most potent compound was 4-amino-5-N-butyl-1-(3-chlorophenyl)-1H-pyrazolo[3,4-d] pyrimidin-6(5H)-one with an IC50 of 6.4 X 10-6 M. Selectivity at the receptor subclasses was examined by performing an A2 adenosine receptor affinity assay with [3H]CGS 21680. This series of compounds were slightly less potent at A2 receptors. 4-Amino-5-N-butyl-1-(3-chlorophenyl)-1H-pyrazolo[3,4-d] pyrimidin-6(5H)-one was the most potent compound with an IC50 of 19.2 X 10-6 M.
- Harden,Quinn,Scammells
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p. 2892 - 2898
(2007/10/02)
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