RESUMO
Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM) have led to the identification of a related series of compounds containing an ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943; Ki = 1.4 nM).
Assuntos
Oxazinas/síntese química , Oxazinas/farmacocinética , Ocitocina/antagonistas & inibidores , Piperidinas/síntese química , Piperidinas/farmacocinética , Animais , Benzoxazinas , Linhagem Celular , Humanos , Concentração Inibidora 50 , Cinética , Ratos , Relação Estrutura-AtividadeRESUMO
The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.
Assuntos
Oxazinas , Piridinas , Receptores de Ocitocina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cães , Feminino , Humanos , Rim/citologia , Rim/embriologia , Rim/metabolismo , Fígado/metabolismo , Masculino , Espectrometria de Massas , Oxazinas/síntese química , Oxazinas/metabolismo , Oxazinas/farmacocinética , Oxazinas/farmacologia , Gravidez , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptores de Ocitocina/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Espectrofotometria Ultravioleta , Contração Uterina/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/fisiologiaRESUMO
Structure-activity studies on the oxytocin antagonist 1 (L-371,257) have identified a new series of high affinity, receptor-selective OT antagonists in which the N-acetyl-4-piperidinyl ether terminus in 1 has been replaced with a 1-(aryl)ethoxy group.
Assuntos
Oxazinas/farmacologia , Ocitocina/antagonistas & inibidores , Piperidinas/farmacologia , Administração Oral , Animais , Benzoxazinas , Disponibilidade Biológica , Feminino , Humanos , Ratos , Relação Estrutura-AtividadeAssuntos
Oxazinas/farmacologia , Ocitocina/antagonistas & inibidores , Piperidinas/farmacologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzoxazinas , Disponibilidade Biológica , Feminino , Humanos , Cinética , Estrutura Molecular , Trabalho de Parto Prematuro/tratamento farmacológico , Oxazinas/química , Oxazinas/farmacocinética , Piperidinas/química , Piperidinas/farmacocinética , Gravidez , Ratos , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Contração Uterina/efeitos dos fármacosRESUMO
A series of new o-tolylpiperazine camphorsulfonamide OT antagonists is described. Analogs containing conformationally constrained 1-acylamino-2-propyl substituents at the camphor C2 endo position exhibit high affinity for OT and AVP-V1a receptors or high affinity and selectivity for OT receptors, depending on functionalities present in the acyl group. Determination of the preferred conformation of potency-enhancing 1-acylamino-2-propyl substituents using molecular mechanics energy calculations and X-ray crystallography, along with topological similarities to a conformationally constrained cyclic hexapeptide OT antagonist, suggests a receptor-bound conformation for this series of non-peptide OT antagonists.
Assuntos
Cânfora/análogos & derivados , Ocitocina/antagonistas & inibidores , Piperazinas/síntese química , Piperazinas/farmacologia , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Sequência de Aminoácidos , Animais , Cânfora/química , Cânfora/farmacologia , Feminino , Humanos , Rim/metabolismo , Cinética , Fígado/metabolismo , Masculino , Modelos Moleculares , Conformação Molecular , Dados de Sequência Molecular , Ocitocina/metabolismo , Piperazinas/química , Ratos , Receptores de Vasopressinas/efeitos dos fármacos , Receptores de Vasopressinas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Trítio , Contração Uterina/efeitos dos fármacos , Útero/metabolismoRESUMO
Non-peptide antagonists of the peptide hormone oxytocin (OT) with nanomolar OT receptor affinities are described. These compounds incorporate novel amido- and amidoalkylcamphor variations to the lead structure L-366,509 (1) to achieve receptor affinity enhancements of 2-3 orders of magnitude over that compound. The new OT antagonist L-367,773 (35) is shown to be an orally bioavailable agent with good duration in vivo and to inhibit OT-stimulated uterine contractions effectively in several in vitro and in vivo models.