RESUMEN
The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K(i) in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Electromiografía/métodos , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Ratas , Receptores de Glutamato Metabotrópico/fisiología , Relación Estructura-ActividadRESUMEN
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
The design and profile of a series of adamantyl-containing long acting beta(2)-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/farmacología , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacología , Adamantano/farmacocinética , Administración por Inhalación , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacocinética , Animales , Cobayas , Humanos , Tráquea/efectos de los fármacosRESUMEN
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.
Asunto(s)
Agonistas del Receptor de Adenosina A2 , Adenosina/análogos & derivados , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Adenosina/farmacocinética , Adenosina/farmacología , Administración por Inhalación , Administración Oral , Aminas/farmacocinética , Aminas/farmacología , Animales , Cobayas , Humanos , Pulmón/metabolismo , Fenetilaminas/farmacocinética , Fenetilaminas/farmacología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The broad spectrum anti-inflammatory actions of adenosine A(2A) receptor agonists are well described. The wide distribution of this receptor, however, suggests that the therapeutic potential of these agents is likely to reside in topical treatments to avoid systemic side effects associated with oral administration. Adenosine A(2A) receptor agonists have been assessed as topical agents: GW328267X (GSK; allergic rhinitis and asthma), UK-432097 (Pfizer; chronic obstructive pulmonary disease [COPD]) and Sonedenoson (MRE0094, King Pharmaceuticals; wound healing). All trials failed to achieve effects against the desired clinical end points. This broad-based review will discuss general principles of chemical design of topically applied agents and potential therapeutic topical applications of current adenosine A(2A) receptor agonists. Potential factors contributing to the lack of efficacy in the above clinical trials will be discussed together with design principles, which may influence efficacy in disease states. Our analysis suggests that adenosine A(2A) receptor agonists have a wide therapeutic potential as topical agents in a wide variety of diseases, such as neutrophil-dependent lung diseases (acute lung injury, exacerbations in asthma and COPD), allergic rhinitis, glaucoma and wound repair. Factors that will influence topical activity include formulation, tissue retention, compound potency, receptor kinetics and pharmacokinetics.
RESUMEN
The design and profile of a series of indole containing long acting beta(2)-adrenoceptor agonists is described. Evaluation of these analogues using an in vitro guinea pig trachea tissue model demonstrates that analogues within this series have salmeterol-like duration of action with potential for long duration of action in humans.
Asunto(s)
Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacología , Asma/tratamiento farmacológico , Indoles/química , Indoles/farmacología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores Adrenérgicos beta 2/efectos de los fármacos , Agonistas Adrenérgicos beta/farmacocinética , Albuterol/análogos & derivados , Albuterol/química , Albuterol/farmacología , Animales , Disponibilidad Biológica , Células CHO , Células CACO-2 , Cricetinae , Cricetulus , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Cobayas , Humanos , Indoles/farmacocinética , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Modelos Moleculares , Estructura Molecular , Ratas , Xinafoato de Salmeterol , Factores de Tiempo , Tráquea/efectos de los fármacosRESUMEN
The design and profile of a series of saligenin containing long acting beta(2)-adrenoreceptor agonists is described. Evaluation of these analogues using a guinea-pig tissue model demonstrates that analogues within this series have significantly longer durations of action than salmeterol and have the potential for a once daily profile in human.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 1 , Agonistas Adrenérgicos beta/farmacología , Animales , Células CACO-2 , Humanos , RatonesRESUMEN
A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability.