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
A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.
Asunto(s)
Azetidinas/síntesis química , Broncodilatadores/síntesis química , Ácidos Difenilacéticos/síntesis química , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptor Muscarínico M3/antagonistas & inhibidores , Administración por Inhalación , Animales , Azetidinas/química , Azetidinas/farmacología , Broncodilatadores/química , Broncodilatadores/farmacología , Células CHO , Línea Celular , Permeabilidad de la Membrana Celular , Cricetinae , Cricetulus , Ácidos Difenilacéticos/química , Ácidos Difenilacéticos/farmacología , Perros , Femenino , Cobayas , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Cinética , Masculino , Microsomas Hepáticos/metabolismo , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Ensayo de Unión Radioligante , Ratas , Receptor Muscarínico M3/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tráquea/efectos de los fármacos , Tráquea/fisiologíaRESUMEN
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.