RESUMEN
Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.
Asunto(s)
Imidazoles/química , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/antagonistas & inhibidores , Piridinas/química , Piridonas/química , Enfermedades Respiratorias/tratamiento farmacológico , Administración por Inhalación , Animales , Humanos , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/química , Inhibidores de las Cinasas Janus/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ratas , Relación Estructura-ActividadRESUMEN
Thymic stromal lymphopoietin (TSLP) is a cytokine released by human lung epithelium in response to external insult. Considered as a master switch in T helper 2 lymphocyte (Th2) mediated responses, TSLP is believed to play a key role in allergic diseases including asthma. The aim of this study was to use a phenotypic approach to identify new biological and chemical starting points for inhibition of TSLP production in human bronchial epithelial cells (NHBE), with the objective of reducing Th2-mediated airway inflammation. To this end, a phenotypic screen was performed using poly I:C / IL-4 stimulated NHBE cells interrogated with a 44,974 compound library. As a result, 85 hits which downregulated TSLP protein and mRNA levels were identified and a representative subset of 7 hits was selected for further characterization. These molecules inhibited the activity of several members of the MAPK, PI3K and tyrosine kinase families and some of them have been reported as modulators of cellular phenotypic endpoints like cell-cell contacts, microtubule polymerization and caspase activation. Characterization of the biological profile of the hits suggested that mTOR could be a key activity involved in the regulation of TSLP production in NHBE cells. Among other targeted kinases, inhibition of p38 MAPK and JAK kinases showed different degrees of correlation with TSLP downregulation, while Syk kinase did not seem to be related. Overall, inhibition of TSLP production by the selected hits, rather than resulting from inhibition of single isolated targets, appeared to be due to a combination of activities with different levels of relevance. Finally, a hit expansion exercise yielded additional active compounds that could be amenable to further optimization, providing an opportunity to dissociate TSLP inhibition from other non-desired activities. This study illustrates the potential of phenotypic drug discovery to complement target based approaches by providing new chemistry and biology leads.
Asunto(s)
Citocinas/antagonistas & inhibidores , Descubrimiento de Drogas , Pulmón/efectos de los fármacos , Células Cultivadas , Citocinas/biosíntesis , Células Epiteliales/efectos de los fármacos , Humanos , Pulmón/citología , Pulmón/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Linfopoyetina del Estroma TímicoRESUMEN
A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure-kinetic relationships (SKR) opened up the possibility of long receptor residence times.
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 , Concentración de Iones de Hidrógeno , Microsomas Hepáticos/metabolismo , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.
Asunto(s)
Acetatos/química , Acetatos/farmacología , Piperidinas/química , Pirazoles/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Acetatos/síntesis química , Acetatos/farmacocinética , Administración Oral , Animales , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Semivida , Humanos , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relación Estructura-ActividadRESUMEN
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
A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.
Asunto(s)
Benzamidas/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Cristalografía por Rayos X , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Crystallographic structural information was used in the design and synthesis of a number of bioisosteric derivatives to replace the amide moiety in a lead series of p38α inhibitors which showed general hydrolytic instability in human liver preparations. Triazole derivative 13 was found to have moderate bioavailability in the rat and demonstrated potent in-vivo activity in an acute model of inflammation.
Asunto(s)
Amidas/química , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Enlace de Hidrógeno , Indoles/química , Indoles/farmacocinética , Inhibidores de Proteínas Quinasas/química , RatasRESUMEN
Optimisation of a series of indolin-2-one p38α inhibitors was achieved via both blocking of a potential metabolic 'hot spot' and by increasing overall polarity of the lead series leading to non-cytotoxic compounds which showed improved oral bioavailabilities in the rat.
Asunto(s)
Indoles/farmacología , Proteína Quinasa 14 Activada por Mitógenos/análisis , Animales , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Estructura Molecular , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The use of structure-based design and molecular modeling led to the discovery of indolin-2-one derivatives as potent and selective p38α inhibitors. The predicted binding mode was confirmed by X-ray crystallography.
Asunto(s)
Diseño de Fármacos , Indoles/química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Microsomas Hepáticos/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Ratas , Relación Estructura-ActividadRESUMEN
The structure-activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.
RESUMEN
The synthesis and SAR of a series of N-(5,6-diarylpyridin-2-yl)amide derivatives as potent A(2B) adenosine receptor antagonists is described. Several compounds showed good selectivity versus other adenosine receptors. The potent and selective analogue 9 was shown to have good oral bioavailability in the rat.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Amidas/química , Antiasmáticos/química , Piridinas/química , Pirimidinas/química , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Animales , Antiasmáticos/síntesis química , Antiasmáticos/farmacocinética , Descubrimiento de Drogas , Humanos , Microsomas Hepáticos/metabolismo , Piridinas/síntesis química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Receptor de Adenosina A2B/metabolismo , Relación Estructura-ActividadRESUMEN
Several new potent and selective A(2B) adenosine receptor antagonists have been prepared in which the aryl-amide moiety of the lead series, exemplified by 1a, has been replaced by bioisosteric bicyclic moieties. Although the majority of compounds had generally improved microsomal stability as compared to 1a, this was not translated into overall improvements in the pharmacokinetic profiles of a representative set of compounds.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Amidas/química , Antiinflamatorios/química , Compuestos Bicíclicos con Puentes/química , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacocinética , Descubrimiento de Drogas , Humanos , Microsomas Hepáticos/metabolismo , NADP/metabolismo , Ratas , Receptor de Adenosina A2B/metabolismoRESUMEN
Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.
Asunto(s)
Amidas , Piperidinas , Serina Endopeptidasas/efectos de los fármacos , Administración Oral , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores del Factor Xa , Humanos , Hígado/enzimología , Modelos Moleculares , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Conformación Proteica , Ratas , Proteínas Recombinantes/efectos de los fármacos , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad , TriptasasRESUMEN
The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.