- GluN2A-selective pyridopyrimidinone series of nmdar positive allosteric modulators with an improved in vivo profile
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The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (1), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure-activity relationships, despite the structural similarity to GNE-0723. GNE-5729 (13), a pyridopyrimidinone-based NMDAR PAM, was identified with both an improved pharmacokinetic profile and increased selectivity against AMPARs. We also include X-ray structure analysis and modeling to propose hypotheses for the activity and selectivity differences.
- Villemure, Elisia,Volgraf, Matthew,Jiang, Yu,Wu, Guosheng,Ly, Cuong Q.,Yuen, Po-Wai,Lu, Aijun,Luo, Xifeng,Liu, Mingcui,Zhang, Shun,Lupardus, Patrick J.,Wallweber, Heidi J. A.,Liederer, Bianca M.,Deshmukh, Gauri,Plise, Emile,Tay, Suzanne,Wang, Tzu-Ming,Hanson, Jesse E.,Hackos, David H.,Scearce-Levie, Kimberly,Schwarz, Jacob B.,Sellers, Benjamin D.
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- Design, synthesis and anti-HBV activity evaluation of new substituted imidazo[4,5-b]pyridines
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The design and synthesis of a number of new imidazo[4,5-b]pyridines is described. The heterocyclic scaffold possesses 6-chloro- or 5,6-dichloro-substitution and bears various 2-alkylamino-methyl or ethyl groups. The corresponding N1 and N3-tosylates are also presented. The anti-HBV activity of the compounds was evaluated in HBV infectious system at the level of HBV rcDNA secretion and CC50, EC50 and selectivity index values were determined. The tosylates showed low antiviral potency and relatively high cytotoxicity, on the contrary, a number of 2,5 and/or-6-substituted imidazopyridines, mainly those belonging to the 6-chloroimidazo[4,5-b]pyridine series, were endowed with a very interesting profile and were further investigated. The most promising among them, along with the reduction of the secreted HBV rcDNA, also caused a reduction in HBV cccDNA and pgRNA levels, with a concomitant accumulation of the intracellular encapsidated rcDNA. Surprisingly, the most active 2-diethylaminoethyl-substituted derivative (21d), was highly competitive to interferon.
- Gerasi, Maria,Frakolaki, Efseveia,Papadakis, Georgios,Chalari, Anna,Lougiakis, Nikolaos,Marakos, Panagiotis,Pouli, Nicole,Vassilaki, Niki
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- Synthesis of new imidazopyridine nucleoside derivatives designed as maribavir analogues
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The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure-activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scafflold. We have thus synthesized a number of novel amino substituted imidazopyridine nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir and have evaluated their potential antiviral activity. The target compounds were synthesized upon glycosylation of suitably substituted 2-aminoimidazopyridines, which were prepared in six steps starting from 2-amino-6-chloropyridine. Even if the new compounds possessed only a slight structural modification when compared to the original drug, they were not endowed with interesting antiviral activity. Even so, three derivatives showed promising cytotoxic potential.
- Papadakis, Georgios,Gerasi, Maria,Snoeck, Robert,Marakos, Panagiotis,Andrei, Graciela,Lougiakis, Nikolaos,Pouli, Nicole
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- SHP2 PHOSPHATASE INHIBITORS AND METHODS OF USE THEREOF
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The present disclosure relates to novel compounds including formula (X) and pharmaceutical compositions thereof, and methods for inhibiting the activity of SHP2 phosphatase with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with SHP2 deregulation with the compounds and compositions of the disclosure.
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Paragraph 0237
(2019/10/15)
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- PYRIDOPYRIMIDINONES AND THEIR USE AS NMDA RECEPTOR MODULATORS
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The invention relates to pyridopyrimidinone compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein X, R, R2, R3, R4, R5 and R6 are as defined herein, as well as pharmaceutical compositions comprising such compounds, useful as NMDA receptor modulators in the treatment of neurological and psychiatric conditions.
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Page/Page column 28
(2016/10/31)
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- Α 7 as intranuclear hydroxynicotinic acetylcholine receptor quinuclidines compd.
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PROBLEM TO BE SOLVED: To provide ligands for the nicotinic α-7 receptor used for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.SOLUTION: The disclosure provides compounds of the specified formula I, including their salts, and compositions and methods using the compounds.
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- Diverse heterocyclic scaffolds as allosteric inhibitors of AKT
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Wide-ranging exploration of potential replacements for a quinoline-based inhibitor of activation of AKT kinase led to number of alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, and one such compound demonstrated pharmacodynamic knockdown of phosphorylation of AKT and downstream biomarkers in vivo and inhibition of tumor growth in a breast cancer xenograft model.
- Kettle, Jason G.,Brown, Simon,Crafter, Claire,Davies, Barry R.,Dudley, Phillippa,Fairley, Gary,Faulder, Paul,Fillery, Shaun,Greenwood, Hannah,Hawkins, Janet,James, Michael,Johnson, Keith,Lane, Clare D.,Pass, Martin,Pink, Jennifer H.,Plant, Helen,Cosulich, Sabina C.
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p. 1261 - 1273
(2012/04/10)
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