RESUMEN
Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.
Asunto(s)
Acetatos/química , Compuestos Bicíclicos con Puentes/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Acetatos/síntesis química , Acetatos/farmacocinética , Animales , Semivida , Humanos , Indoles/química , Inyecciones Intravenosas , Ratas , Ratas Wistar , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relación Estructura-ActividadRESUMEN
The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ≠ H) gives access to compounds with dissociation half-lives of ⩾ 24h.
Asunto(s)
Acetatos/química , Compuestos Bicíclicos con Puentes/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Acetatos/síntesis química , Acetatos/farmacocinética , Semivida , Humanos , Enlace de Hidrógeno , Modelos Químicos , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relación Estructura-ActividadRESUMEN
High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.
Asunto(s)
Acetatos/química , Pirazoles/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Acetatos/síntesis química , Acetatos/farmacocinética , Animales , Semivida , Ensayos Analíticos de Alto Rendimiento , Unión Proteica , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relación Estructura-ActividadRESUMEN
Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.
Asunto(s)
Naftiridinas/síntesis química , Naftiridinas/farmacología , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/farmacología , Administración por Inhalación , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhaladores de Polvo Seco , Lipopolisacáridos/farmacología , Pulmón/metabolismo , Masculino , Naftiridinas/administración & dosificación , Neutrófilos/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times.
Asunto(s)
Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Sulfonas/química , Sulfonas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Cinética , Estructura Molecular , Relación Estructura-Actividad , Sulfonas/síntesis químicaRESUMEN
Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.
Asunto(s)
Compuestos de Bifenilo/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Piridazinas/farmacología , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/química , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Piridazinas/síntesis química , Piridazinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
[reaction: see text] A new stereodivergent route to erythro- and threo-beta-substituted serines from a common C(2)-symmetrical alk-2-yne-1,4-diol is described. Stereocontrol in such an acyclic system is achieved by taking advantage of symmetry. Stereoselective alkyne reduction to either (Z)- or (E)-olefin allows selection of the stereochemistry of alpha-carbon in the final amino acid by using a Pd(0)-catalyzed process. This strategy has been applied to the synthesis of (2S,3S)-3-hydroxyleucine.
Asunto(s)
Aminoácidos/química , Aminoácidos/síntesis química , Catálisis , Ciclización , Leucina/análogos & derivados , Leucina/síntesis química , Leucina/química , Conformación Molecular , Serina/análogos & derivados , Serina/síntesis química , Serina/químicaRESUMEN
In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl benzyl substituents was found, from which compounds 27 and 63 were advanced to in vivo profiling.