Structure−Activity Relationships in Platelet-Activating Factor (PAF). 10. From PAF Antagonism to Inhibition of HIV-1 Replication

• Published in: Journal of medicinal chemistry 2000-06, Vol.43 (11), p.2149-2154
• Main Authors: Serradji, Nawal, Bensaid, Okkacha, Martin, Marc, Kan, Erwan, Dereuddre-Bosquet, Nathalie, Redeuilh, Catherine, Huet, Jack, Heymans, Françoise, Lamouri, Aazdine, Clayette, Pascal, Dong, Chang Zhi, Dormont, Dominique, Godfroid, Jean-Jacques
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cells, Cultured; HIV - drug effects; HIV - physiology; Human immunodeficiency virus 1; Humans; In Vitro Techniques; Inhibitory Concentration 50; Macrophages - drug effects; Macrophages - virology; Medical sciences; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Platelet Activating Factor - antagonists & inhibitors; Platelet Membrane Glycoproteins - antagonists & inhibitors; platelet-activating factor; platelet-activating factor antagonists; PMS 601; Pyridines - pharmacology; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Thiazoles - pharmacology; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9911276

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 IC50 of 8 and 11 μM for anti-PAF and anti-HIV activity, respectively, without cytotoxic events at 1000 μM 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.