title: Structure-activity relationships in platelet-activating factor. 12. Synthesis and biological evaluation of platelet-activating factor antagonists with anti-HIV-1 activity.
abstract: 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.
authors.affiliation: Unité de Recherche Pharmacochimie Moléculaire et Systèmes Membranaires, Laboratoire de Pharmacochimie Moléculaire, Université Paris 7-Denis Diderot, 2 Place Jussieu, 75251 Paris Cedex 05, France.
authors.forename: Nawal
authors.initials: N
authors.lastname: Serradji
authors.forename: Marc
authors.initials: M
authors.lastname: Martin
authors.forename: Okkacha
authors.initials: O
authors.lastname: Bensaid
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.forename: Christophe
authors.initials: C
authors.lastname: Rousselle
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dereuddre-Bosquet
authors.forename: Jack
authors.initials: J
authors.lastname: Huet
authors.forename: Catherine
authors.initials: C
authors.lastname: Redeuilh
authors.forename: Aazdine
authors.initials: A
authors.lastname: Lamouri
authors.forename: Chang-Zhi
authors.initials: CZ
authors.lastname: Dong
authors.forename: Pascal
authors.initials: P
authors.lastname: Clayette
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.forename: Dominique
authors.initials: D
authors.lastname: Dormont
authors.forename: Françoise
authors.initials: F
authors.lastname: Heymans
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D008297:Male; D051379:Mice; D010539:Permeability; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; C410215:PMS 601; D010879:Piperazines; D010972:Platelet Activating Factor