Structure-activity relationships in platelet-activating factor. 12. Synthesis and biological evaluation of platelet-activating factor antagonists with anti-HIV-1 activity
| Autor: | Françoise Heymans, Salvatore Cisternino, Nathalie Dereuddre-Bosquet, Catherine Redeuilh, Nawal Serradji, Jack Huet, Dominique Dormont, Marc Martin, Chang-Zhi Dong, Jean-Michel Scherrmann, Christophe Rousselle, Okkacha Bensaid, Aazdine Lamouri, Pascal Clayette |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Platelet Aggregation Anti-HIV Agents Central nervous system Biological Availability Pharmacology In Vitro Techniques Blood–brain barrier Virus Replication Permeability Piperazines Rats Sprague-Dawley chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery medicine Potency Neurotoxin Animals Humans Platelet Activating Factor Cells Cultured Platelet-activating factor Microglia Macrophages Antagonist In vitro Rats medicine.anatomical_structure chemistry Blood-Brain Barrier Immunology HIV-1 Molecular Medicine Carbamates Rabbits |
| Zdroj: | Journal of medicinal chemistry. 47(25) |
| ISSN: | 0022-2623 |
| Popis: | The HIV-1 central nervous system infection leads to the onset of neurological impairments called AIDS dementia complex (ADC). PAF plays an important role in this pathology, as it is an HIV-1-induced neurotoxin produced by infected or activated macrophages and microglia, in the brain. We previously reported that PAF-antagonists bearing a trisubstituted piperazine presented in vitro anti-HIV-1 activity in human macrophages. To improve the pharmacological activities of our lead compound, 1a, we modified its carbamate function and evaluated both its antiretroviral and anti-PAF activities. One carbamate derivative (10c) demonstrated a similar antiviral activity but a higher anti-PAF potency, whereas 4a, with an ureide function, presents an increased antiviral activity and can be considered as a pure antiretroviral drug, as it does not present PAF-antagonism. Moreover, we measured the ability of 1a to cross the blood-brain barrier, using the in situ mouse brain perfusion method and its plasmatic concentrations after iv and po administration. The transport parameter measured (K(in)) proves that 1a is able to cross this biological barrier, but a pharmacokinetic study reveals its weak bioavailability in rats. |
| Databáze: | OpenAIRE |
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