- Design and synthesis of 3-aminophthalazine derivatives and structural analogues as PDE5 inhibitors: anti-allodynic effect against neuropathic pain in a mouse model
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Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC50 = 3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole)were evaluated in comparison to MY 5445 (4b)in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment.
- Bollenbach, Maud,Lugnier, Claire,Kremer, Mélanie,Salvat, Eric,Megat, Salim,Bihel, Frédéric,Bourguignon, Jean-Jacques,Barrot, Michel,Schmitt, Martine
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p. 269 - 290
(2019/06/05)
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- OXADIAZINE COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure relates to oxadiazine compounds, pharmaceutical compositions comprising an effective amount of an oxadiazine compound and methods for using an oxadiazine compound in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of an oxadiazine compound.
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Paragraph 0764
(2017/03/14)
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- THERAPEUTIC COMPOUNDS
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Compounds disclosed herein including compounds of formula I′: and salts thereof are provided. Pharmaceutical compositions comprising compounds disclosed herein, processes for preparing compounds disclosed herein, intermediates useful for preparing compounds disclosed herein and therapeutic methods for treating an HIV infection using compounds disclosed herein are also provided.
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Paragraph 1088
(2013/11/05)
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- Direct access to 3-aminoindazoles by Buchwald-Hartwig C-N coupling reaction
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An efficient synthesis of various N-substituted 3-aminoindazoles using Buchwald-Hartwig C-N coupling reaction is described. Several parameters were varied, including the nature of the halogen atom and the protecting group of the starting materials, as well as the effects of the catalyst system, base, solvent, and reaction time. The efficiency of microwave versus conventional heating was also compared to test the outcome of the reaction. Thus, by applying this recent knowledge about metal-catalyzed aminations, an alternative for the direct synthesis of primary 3-aminoindazoles has been provided. Georg Thieme Verlag Stuttgart. New York.
- Lohou, Elodie,Collot, Valeri,Stiebing, Silvia,Rault, Sylvain
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experimental part
p. 2651 - 2663
(2011/10/04)
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