- METHODS AND TOOLS FOR THE THERAPY OF NEURODEGENERATIVE PATHOLOGIES
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The present invention concerns compositions and methods for the treatment of neurodegenerative diseases in which the cognitive functions are altered, such as observed in Alzheimer's disease. More particularly, the invention presents a strategy for human clinical monitoring of the activity and/or effectiveness of neuroprotective treatments, based on biochemical assay of certain platelet parameters, and thus can be done by blood sampling. The invention also concerns methods, tools, constructions and compositions suitable for implementing these strategies
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- Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors
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Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-α production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.
- Hamblin, J. Nicole,Angell, Tony D.R.,Ballantine, Stuart P.,Cook, Caroline M.,Cooper, Anthony W.J.,Dawson, John,Delves, Christopher J.,Jones, Paul S.,Lindvall, Mika,Lucas, Fiona S.,Mitchell, Charlotte J.,Neu, Margarete Y.,Ranshaw, Lisa E.,Solanke, Yemisi E.,Somers, Don O.,Wiseman, Joanne O.
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scheme or table
p. 4237 - 4241
(2009/04/07)
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- Molecular target of neurotoxicity
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The present invention relates to the fields of biology, genetics and medicine. In particular it concerns new methods for the detection, characterisation and/or treatment (or management) of neurodegenerative diseases, particularly amyotrophic lateral sclerosis. The invention equally concerns methods for identifying or screening compounds active in these diseases. The invention further concerns the compounds, genes, cells, plasmids or compositions useful for implementing the hereinabove methods. In particular, the invention describes the role of PDE4B in these diseases and its use as a therapeutic, diagnostic or experimental target.
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- Imidazole derivatives and salts thereof
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1-Substituted-imidazoles of the formula: STR1 in which A is selected from the group consisting of straight or branched, saturated or unsaturated, acyclic hydrocarbon radicals of from 1 to 3 carbon atoms and R is STR2 wherein n is an integer which is at least 1, and the or each Q substituent, which when n is greater than 1 may be the same or different, is selected from a saturated alkyl group of from 1 to 4 carbon atoms or an unsaturated alkyl group of from 2 to 4 carbon atoms, with the proviso that when A is unsaturated Q may also be selected from alkoxy of from 1 to 4 carbon atoms; halo; trihalomethyl; hydroxy; carboxyl; a salt of such a carboxyl group; carboalkyloxy; carboaryloxy; carboarylalkyloxy; --NR6 R7 or --CONR6 R7 ; in which R6 and R7 may be the same or different and are hydrogen or alkyl of from 1 to 4 carbon atoms; the 1-substituted-imidazole being the free base or an acid addition salt thereof. Methods of preparing the 1-substituted-imidazoles are also provided. The imidazoles have pharmacological properties that make them of use in the treatment of thromboembolic disorders, shock and angina pectoris.
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- Treatment of shock
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The invention relates to a class of imidazoles substituted by cycloalkyl or cycloalkenyl which have pharmacological properties making them useful in medicine, in particular in the prophylaxis and treatment of thrombo-embolic disorders, and also of shock and angina pectoris.
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- Pharmaceutical compositions
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Pharmaceutical combinations comprising (a) prostacyclin, dihydroprostacyclin or a pharmaceutically acceptable salt of either of these, and (b) a phosphodiesterase inhibitor. Pharmaceutical formulations comprising a combination as above and a pharmaceutically acceptable carrier. Methods are disclosed for preparing the combinations and the formulations. The combinations and formulations are useful for preventing or minimizing platelet aggregation in blood, blood products or blood substitutes for example in the treatment of thrombosis, gastric lesions and wounds, and in the extra-corporeal circulation of blood and in blood separation processes.
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- Pharmaceutically active imidazole derivatives
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The invention relates to a class of imidazoles substituted by cycloalkyl or cycloalkenyl which have pharmacological properties making them useful in medicine, in particular in the prophylaxis and treatment of thrombo-embolic disorders.
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- Amino derivatives of pyrazolopyridine carboxamides
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4-Amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxamides having the formula SPC1 Are disclosed. The novel compounds are useful as ataractic, analgesic, and hypotensive agents.
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