ABSTRACT
Integration of viral DNA into the host cell genome is an obligatory process for successful replication of HIV-1. Integrase catalyzes the insertion of viral DNA into the target DNA and is a validated target for drug discovery. Herein, we report the synthesis, antiviral activity and pharmacokinetic profiles of several C2-carbon-linked heterocyclic pyrimidinone-4-carboxamides that inhibit the strand transfer step of the integration process.
Subject(s)
Amides/chemistry , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/chemistry , HIV-1/enzymology , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacokinetics , HIV-1/drug effects , Half-Life , Heterocyclic Compounds/chemistry , Humans , Male , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 +/- 3.5 ml/min/kg), volume of distribution (2.6 +/- 0.3 l/kg), and half-life (1.2 +/- 0.2 h) of 6-OH-buspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT)(1A) receptor occupancy in a concentration-dependent manner with EC(50) values of 1.0 +/- 0.3 and 0.38 +/- 0.06 microM in the dorsal raphe and 4.0 +/- 0.6 and 1.5 +/- 0.3 microM in the hippocampus, respectively. Both compounds appeared to be approximately 4-fold more potent in occupying presynaptic 5-HT(1A) receptors in the dorsal raphe than the postsynaptic receptors in the hippocampus. Oral dosing of buspirone in rats resulted in exposures (area under the concentration-time profile) of 6-OH-buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP), another major metabolite of buspirone, that were approximately 12 (6-OH-buspirone)- and 49 (1-PP)-fold higher than the exposure of the parent compound. As a whole, these preclinical data suggest that 6-OH-buspirone probably contributes to the clinical efficacy of buspirone as an anxiolytic agent.
Subject(s)
Buspirone/analogs & derivatives , Buspirone/pharmacokinetics , Receptor, Serotonin, 5-HT1A/metabolism , Animals , Area Under Curve , Autoradiography , Biological Availability , Buspirone/blood , Buspirone/metabolism , Buspirone/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Male , Molecular Structure , Piperazines/metabolism , Prosencephalon/drug effects , Prosencephalon/metabolism , Protein Binding/drug effects , Pyridines/metabolism , Raphe Nuclei/drug effects , Raphe Nuclei/metabolism , Rats , Rats, Sprague-Dawley , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/pharmacology , TritiumABSTRACT
N-[2-[2-(4-Phenylbutyl)benzofuran-4-yl]cyclopropylmethyl]acetamide 3a was synthesized as an orally bioavailable agonist at MT1 and MT2 melatonin receptors with significantly low vasoconstrictive activity.
