RESUMO
We have investigated the structure-activity relationships of the 1- and 3-substituents and replacements of the 5-phenyl group of GW405212X 1, a potent selective oxytocin antagonist. The effect of these modifications on oxytocin binding antagonism and on pharmacokinetic parameters is reported.
Assuntos
Benzodiazepinas/farmacologia , Ocitocina/antagonistas & inibidores , Tocolíticos/síntese química , Administração Oral , Animais , Benzodiazepinas/síntese química , Benzodiazepinas/farmacocinética , Disponibilidade Biológica , Cães , Humanos , Concentração Inibidora 50 , Injeções Intravenosas , Ocitocina/metabolismo , Biblioteca de Peptídeos , Ligação Proteica , Receptores de Ocitocina/metabolismo , Relação Estrutura-Atividade , Tocolíticos/farmacocinética , Tocolíticos/farmacologiaRESUMO
SAR investigations of the 4- and 5-positions of a series of 4-amino-4H-pyran-2-carboxylic acid 6-carboxamides are reported. Potent inhibitors of influenza A sialidase with marked selectivity over the influenza B enzyme were obtained when the basic 4-amino substituent was replaced by hydroxyl or even deleted. Modifications at the 5-position exhibited a tight steric requirement, with trifluoroacetamide being optimal.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Nylons/química , Piranos/química , Ácidos Siálicos/química , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Guanidinas , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/enzimologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/enzimologia , Modelos Moleculares , Estrutura Molecular , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Nylons/farmacologia , Piranos/farmacologia , Ácidos Siálicos/metabolismo , Relação Estrutura-Atividade , Ensaio de Placa Viral , ZanamivirRESUMO
A series of benzophenone derivatives has been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (RT) and the growth of HIV-1 in MT-4 cells. Through the use of the structure-activity relationships within this series of compounds and computational chemistry techniques, a binding conformation is proposed. The SAR also indicated that the major interactions of 1h with the RT enzyme are through hydrogen bonding of the amide and benzophenone carbonyls and pi-orbital interactions with the benzophenone nucleus and an aromatic function separated from the benzophenone by a suitable spacer group. The crystal structure of compound 1h has been determined. A number of compounds with potent inhibitory activity against HIV-1 RT and HIV in cellular assays at levels comparable with AZT and our efforts to identify a metabolically stable analogue are described.
Assuntos
Benzofenonas/farmacologia , HIV-1/enzimologia , Inibidores da Transcriptase Reversa , Linhagem Celular , Cristalografia por Raios X , Resistência Microbiana a Medicamentos , Transcriptase Reversa do HIV , HIV-1/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Reaction of hydroxyl-protected derivatives of hydroxyalkoxyamines (3a,b,c) with either 4,6-dichloro-2,5-diformamidopyrimidine (5) or 4,6-dichloro-5-formamidopyrimidine (31) and subsequent cyclization of the resultant 6-(alkoxyamino)pyrimidines (6, 17, 32, 35) by heating with diethoxymethyl acetate afforded 9-alkoxy-6-chloropurines (7, 18, 33, 36), which were converted subsequently to 9-(3-hydroxypropoxy)- and 9-[3-hydroxy-2-(hydroxymethyl)propoxy] derivatives of guanine, 2-amino-6-chloropurine, 2-amino-6-alkoxypurines, 2-aminopurine, 2,6-diaminopurine, adenine, hypoxanthine, and 6-methoxypurine (8, 12, 13, 19-21, 23-26, 34, 37-39). Carboxylic acid esters (9-11, 14-16, 27-29) and a cyclic phosphate derivative (22) of the 9-(hydroxyalkoxy)guanines (8, 21) and 2-amino-9-(hydroxyalkoxy)purines (13, 26) were also prepared. The guanine derivatives (8, 21) showed potent and selective activity against herpes simplex virus types 1 and 2 and varicella zoster virus in cell cultures and 8 is more active than acyclovir. Although without significant antiviral activity in cell cultures, the 2-aminopurines (13, 14-16, 26-29) and 2-amino-6-alkoxypurines (12, 23-25) are well absorbed after oral administration to mice and are converted efficiently to the antiviral guanine derivatives (8, 21) in vivo.