RESUMEN
In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirrolidinas/química , Pirrolidinas/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Animales , Fosfatidilinositol 3-Quinasa Clase I , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Pruebas de Enzimas/métodos , Humanos , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , RatasRESUMEN
The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes δ, ε, η, θ (in particular PKCε/η, and display a 10-100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCθ-dependent pathways in vitro and in vivo. In vitro, a-CD3/a-CD28-induced lymphocyte proliferation could be effectively blocked in 10% rat whole blood. In mice, 11 dose-dependently inhibited Staphylococcus aureus enterotoxin B-triggered IL-2 serum levels after oral dosing.
Asunto(s)
Naftiridinas/química , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Administración Oral , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Enterotoxinas/toxicidad , Interleucina-2/sangre , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Ratones , Naftiridinas/síntesis química , Naftiridinas/farmacocinética , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Ratas , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
A novel series of pyrazolo[1,5a]pyrimidines was optimized to target lymphocyte-specific kinase (Lck). An efficient synthetic route was developed and SAR studies toward activity and selectivity are described, leading to Lck inhibitors with enzymatic, cellular and in vivo potency.
Asunto(s)
Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Administración Oral , Animales , Humanos , Interleucina-2/metabolismo , Activación de Linfocitos/efectos de los fármacos , Ratones , Microsomas Hepáticos/metabolismo , Pirimidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.