RESUMO
We have previously described a series of antagonists that showed high potency and selectivity for the NK(1) receptor. However, these compounds also had the undesirable property of existing as a mixture of interconverting rotational isomers. Here we show that alteration of the 2-naphthyl substituent can modulate the rate of isomer exchange. Comparisons of the NK(1) receptor affinity for the various conformational forms has facilitated the development of a detailed NK(1) pharmacophore model.
Assuntos
Naftalenos/síntese química , Antagonistas dos Receptores de Neurocinina-1 , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular Tumoral , Cães , Gerbillinae , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Naftalenos/química , Naftalenos/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Coelhos , Ensaio Radioligante , Receptores da Neurocinina-1/química , Receptores da Neurocinina-1/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/síntese química , Receptores da Neurocinina-2/antagonistas & inibidores , Sulfóxidos/síntese química , Taquicininas/antagonistas & inibidores , Animais , Disponibilidade Biológica , Cães , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfóxidos/farmacocinética , Sulfóxidos/farmacologiaRESUMO
Addition of phenyllithium to a mixture of an imine, methyl o-iodobenzoate, and BF(3).etherate at -105 degrees C gives good to excellent yields of isoindolones. The transient formation of methyl o-lithiobenzoate is proposed, which is formed by a rapid lithium/iodide exchange reaction of the phenyllithium with methyl o-iodobenzoate in the presence of the imine. The transiently generated anions can then be captured by the BF(3)-activated imines to form the isoindolones in good to high yield. The reactions conditions are sufficiently mild, and selective, to permit functional groups such carbmethoxy and aryl bromide, which could otherwise react with the added PhLi, to be tolerated.