Structure−Activity Relationships in Platelet-Activating Factor (PAF). 10. From PAF Antagonism to Inhibition of HIV-1 Replication
| Autor: | Jack Huet, Marc Martin, Okkacha Bensaid, Erwan Kan, Dominique Dormont, Nathalie Dereuddre-Bosquet, Catherine Redeuilh, Nawal Serradji, Chang-Zhi Dong, Aazdine Lamouri, Pascal Clayette, Jean-Jacques Godfroid, Françoise Heymans |
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| Rok vydání: | 2000 |
| Předmět: |
Anti-HIV Agents
Pyridines Receptors Cell Surface Microbial Sensitivity Tests Platelet Membrane Glycoproteins In Vitro Techniques Pharmacology Virus Replication Piperazines Receptors G-Protein-Coupled Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Mediator Drug Discovery Humans Structure–activity relationship Cytotoxic T cell Platelet Activating Factor Mode of action Receptor Cells Cultured Platelet-activating factor Chemistry Macrophages HIV In vitro Thiazoles Viral replication Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 43:2149-2154 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Excessive levels of PAF and cells of macrophage lineage appear to play an important role in neuronal cell injury, inflammatory syndrome, and HIV replication in CNS resulting in AIDS dementia complex (ADC). The beneficial effects of PAF receptor antagonists are evident and give rise to expected therapeutic strategies for neurotrauma. Piperazine derivatives bearing a "cache-oreilles" (ear-muff) electronic distribution are able to inhibit in vitro PAF effects and, thus, could be used in pathologies where this mediator is involved. Therefore, their potential anti-HIV activity was investigated, and we find that (i) these PAF antagonists are effectively active in HIV-infected monocyte-derived macrophages (MDM) but there is no correlation between both anti-HIV and anti-PAF activities; (ii) the presence of a carbamate function (compounds 1a-d) is favorable to the antiviral activity; (iii) the lipophilicity of the substituent on the piperazinic cycle seems to be less important for the anti-PAF activity than for the antiviral one. Our leading compound, PMS 601 (compound 1a), presents a dual activity with IC(50) of 8 and 11 microM for anti-PAF and anti-HIV activity, respectively, without cytotoxic events at 1000 microM in MDM. Although its mode of action is not clearly defined, these data suggest that PMS 601, which displays no effect on acellular reverse transcriptase or protease tests, deserves further investigation in the treatment of HIV-1-associated dementia. |
| Databáze: | OpenAIRE |
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