RESUMO
The preparation and characterization of a series of selective glucocorticoid receptor modulators are described. The preliminary structure-activity relationship of nonaromatic C-5 substitution on the tetracyclic quinoline core showed a preference for small lipophilic side chains. Proper substitution at this position maintained the transcriptional repression of proinflammatory transcription factors while diminishing the transcriptional activation activity of the ligand/glucocorticoid receptor complex. The optimal compounds described in this study were the allyl analogue 18 and cyclopentyl analogue 32. These candidates showed slightly less potent, highly efficacious E-selectin repression with significantly reduced levels of glucocorticoid response element activation in reporter gene assays vs prednisolone. Allyl analogue 18 was evaluated in vivo. An oral dose of 18 showed an ED(50) = 1.7 mg/kg as compared to 1.2 mg/kg for prednisolone in the Sephadex-induced pulmonary eosinophilia model and an ED(50) = 15 mg/kg vs 4 mg/kg for prednisolone in the carrageenan-induced paw edema model.
Assuntos
Benzopiranos/síntese química , Quinolinas/síntese química , Receptores de Glucocorticoides/efeitos dos fármacos , Animais , Benzopiranos/química , Benzopiranos/farmacologia , Ligação Competitiva , Carragenina , Linhagem Celular , Chlorocebus aethiops , Depressão Química , Selectina E/genética , Selectina E/metabolismo , Edema/induzido quimicamente , Edema/patologia , Eosinófilos/patologia , Genes Reporter , Humanos , Insetos , Luciferases/genética , Luciferases/metabolismo , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Pneumonia/patologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Elementos de Resposta , Relação Estrutura-Atividade , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
The primary goal of this study is to examine the association between marijuana use and adult depressive symptomatology. The key independent variables examined are age of marijuana initiation, frequency of current marijuana use, the use of other licit and illicit drugs, and whether marijuana was used to cope with problems. The relationships among these variables are assessed using data from the Young Men and Drugs Survey (n = 1,941), a nationally representative sample of men from the 1944-1954 birth cohort. Results show that early marijuana initiation appears to be weakly associated with increased depression in adulthood. This effect, however, is mediated by educational attainment, employment status, marital status, and other drug use, notably alcohol and tobacco use. Adult frequency of marijuana use is not significantly associated with increased depression in adulthood. Finally, marijuana users who use the drug to cope with problems are more depressed than those who do not use to cope with problems.
Assuntos
Depressão/complicações , Fumar Maconha/efeitos adversos , Adaptação Psicológica , Adulto , Depressão/psicologia , Humanos , MasculinoRESUMO
The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 microM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
Assuntos
Inibidores da Protease de HIV/química , Protease de HIV/metabolismo , Ritonavir/análogos & derivados , Ritonavir/química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Protease de HIV/química , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/farmacologia , Taxa de Depuração Metabólica , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Conformação Proteica , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Ritonavir/farmacocinética , Ritonavir/farmacologia , Solubilidade , Relação Estrutura-AtividadeRESUMO
The 2-isopropyl thiazolyl group is a highly optimized P3 ligand for C2 symmetry-based HIV protease inhibitors, as exemplified in the drug ritonavir. Here we report that incorporation of this P3 ligand into a piperazine hydroxyethylamine series also yielded novel, highly potent inhibitors. In tissue culture assays, the presence of human serum was less deleterious to the activity of these inhibitors than to that of ritonavir. Furthermore, potent activity against ritonavir resistant HIV was observed.
Assuntos
Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Sangue , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , HIV/efeitos dos fármacos , Inibidores da Protease de HIV/síntese química , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/enzimologia , Oxigenases de Função Mista/antagonistas & inibidores , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologiaRESUMO
Equine infectious anemia virus (EIAV) was injected intrathoracically into Aedes aegypti, Stomoxys calcitrans, and Tabanus fuscicostatus, and fed to Ae. aegypti in suspensions of either artificial blood of Eagle's Minimum Essential Medium. Insects were stored at -70 degrees C for up to 9 months before testing for the presence of EIAV. The viral tissue culture titers detected from stored insects were similar to those from insects tested at time 0.
Assuntos
Aedes/virologia , Dípteros/virologia , Vírus da Anemia Infecciosa Equina/isolamento & purificação , Muscidae/virologia , Animais , CongelamentoRESUMO
Examination of the structural basis for antiviral activity, oral pharmacokinetics, and hepatic metabolism among a series of symmetry-based inhibitors of the human immunodeficiency virus (HIV) protease led to the discovery of ABT-538, a promising experimental drug for the therapeutic intervention in acquired immunodeficiency syndrome (AIDS). ABT-538 exhibited potent in vitro activity against laboratory and clinical strains of HIV-1 [50% effective concentration (EC50) = 0.022-0.13 microM] and HIV-2 (EC50 = 0.16 microM). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC50 for > 12 h. In human trials, a single 400-mg dose of ABT-538 displayed a prolonged absorption profile and achieved a peak plasma concentration in excess of 5 micrograms/ml. These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease.