RESUMEN
In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.
Asunto(s)
Corticoesteroides/síntesis química , Corticoesteroides/farmacocinética , Antiasmáticos/síntesis química , Antiasmáticos/farmacocinética , Asma/tratamiento farmacológico , Diseño de Fármacos , Administración por Inhalación , Corticoesteroides/administración & dosificación , Corticoesteroides/farmacología , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/uso terapéutico , Androstadienos/química , Androstadienos/farmacología , Animales , Antiasmáticos/administración & dosificación , Antiasmáticos/farmacología , Asma/epidemiología , Asma/fisiopatología , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Inhaladores de Polvo Seco , Fluticasona , Hepatocitos , Humanos , Hígado , Pulmón , Microsomas Hepáticos , Neutrófilos/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Ratas , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/sangreRESUMEN
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
A bacterium able to utilize sulfamate as N-source for growth was isolated from soil and identified as a Mycobacterium sp. An apparently previously unrecorded enzyme, sulfamate hydrolase (EC 3.10.1.-), converts sulfamate to equimolar amounts of ammonia and sulfate. This enzyme was purified to homogeneity and had a Km for sulfamate of 26.36 +/- 4.01 mM. Its Specificity Constant value, 74 M(-1) s(-1), was low, indicating that it was not a particularly good catalyst for this reaction and it may be a hydrolase recruited to this role from some other reaction sequence. However, under equivalent conditions it showed no detectable action on the other sulfamates, cyclamate and sulfamoylbenzoate, or on urea or methylamine.
