RESUMO
Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores/química , Indanos/farmacologia , Quinolonas/farmacologia , Administração por Inalação , Animais , Cobaias , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indanos/administração & dosagem , Indanos/farmacocinética , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
We report on a new, high-throughput assay designed to measure octanol/water partition coefficients in early drug discovery. The assay is carried out in 96-well microtiterplates and measures the diffusion of compounds between two aqueous compartments separated by a thin octanol liquid layer. Octanol/water partition coefficients are derived from the apparent permeability (P(a)) values using a calibration curve. The assay can measure partition coefficients within the range -2 to + 8; thus, a dynamic range of 10 log units can be covered in one single run. Unlike chromatographic methods, the technology is not restricted to neutral and weakly basic compounds, and, as no stationary phase is involved, the data can be strictly compared with values obtained from traditional methods such as shake-flask/HPLC or dual-phase potentiometric titration.
