RESUMEN
A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/síntesis química , Broncodilatadores/síntesis química , Antagonistas Muscarínicos/síntesis química , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Triazoles/síntesis química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Animales , Disponibilidad Biológica , Broncoconstricción/efectos de los fármacos , Broncodilatadores/farmacocinética , Broncodilatadores/farmacología , Células CHO , Cricetulus , Perros , Humanos , Ipratropio/farmacología , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacología , Ratas , Receptor Muscarínico M3/antagonistas & inhibidores , Xinafoato de Salmeterol/farmacología , Bromuro de Tiotropio/farmacología , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
This paper describes the successful design and development of dual pharmacology ß-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2 , Diseño de Fármacos , Antagonistas Muscarínicos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Animales , Compuestos de Bencidrilo/administración & dosificación , Cresoles/administración & dosificación , Quimioterapia Combinada , Cobayas , Estructura Molecular , Antagonistas Muscarínicos/administración & dosificación , Fenilpropanolamina/administración & dosificación , Tartrato de TolterodinaRESUMEN
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.
Asunto(s)
Agonistas del Receptor de Adenosina A2 , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Adenosina/análogos & derivados , Adenosina/química , Administración por Inhalación , Adolescente , Adulto , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Pulmón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Modelos Químicos , Fenetilaminas/química , Purinas/química , Ratas , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.