RESUMEN
Physicochemical properties, such as solubility, are important when prioritising compounds for progression on a drug discovery project. There is limited literature around the systematic effects of core changes on thermodynamic solubility. This work details the synthesis of nitrogen containing 6,5-bicyclic heterocyclic cores which are common scaffolds in medicinal chemistry and the analysis of their physicochemical properties, particularly, thermodynamic solubility. Crystalline solids were obtained where possible to enable a robust comparison of the thermodynamic solubility. Other parameters such as pKa, melting point and lipophilicity were also measured to determine the key factors affecting the observed solubility.
Asunto(s)
Amidas/química , Compuestos Heterocíclicos con 2 Anillos/química , Nitrógeno/química , Pirimidinas/química , Termodinámica , Amidas/síntesis química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Estructura Molecular , Pirimidinas/síntesis química , SolubilidadRESUMEN
The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIß is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy. Combination of this knowledge showed that a dual covalent inhibitor could be developed which reveals potential in addressing the challenges associated with drug resistant mutations.
RESUMEN
Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Sulfonamidas/farmacología , Animales , Cristalografía por Rayos X , Femenino , Masculino , Ratones Endogámicos BALB C , Estructura Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3/metabolismo , Unión Proteica , Ratas Wistar , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/metabolismoRESUMEN
A novel pyrrole-2-carboxamide series of p38alpha inhibitors, discovered through the application of virtual screening, is presented. Following evaluation of activity, selectivity and developability properties of commercially available analogues, a synthesis program enabled rapid assessment of the series' suitability for further lead optimisation studies.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas Clase III/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Animales , Unión Competitiva , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Isoenzimas , Modelos Moleculares , Simulación del Acoplamiento Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/toxicidad , Ratas , Relación Estructura-ActividadRESUMEN
A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Relación Estructura-Actividad , Administración por Inhalación , Animales , Fosfatidilinositol 3-Quinasa Clase Ia/química , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Enlace de Hidrógeno , Isoquinolinas/química , Células de Riñón Canino Madin Darby , RatasRESUMEN
We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.
RESUMEN
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
Asunto(s)
Indazoles/química , Oxazoles/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Enfermedades Respiratorias/tratamiento farmacológico , Sulfonamidas/química , Administración por Inhalación , Animales , Asma/tratamiento farmacológico , Femenino , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Indoles , Isoenzimas/antagonistas & inhibidores , Masculino , Microsomas/metabolismo , Simulación del Acoplamiento Molecular , Ovalbúmina/inmunología , Oxazoles/farmacocinética , Oxazoles/farmacología , Piperazinas , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Conejos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Células Th2/inmunologíaRESUMEN
The identification and progression of a potent and selective series of isoquinoline inhibitors of IkappaB kinase-beta (IKK-beta) are described. Hit-generation chemistry based on IKK-beta active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-alpha.