RESUMEN
Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.
Asunto(s)
Oxadiazoles/farmacología , Receptores de Lisoesfingolípidos/agonistas , Tiadiazoles/farmacología , Animales , Encéfalo/metabolismo , Ácido Glutámico/metabolismo , Células Hep G2 , Humanos , Enlace de Hidrógeno , Cinética , Oxadiazoles/sangre , Oxadiazoles/síntesis química , Ratas , Solubilidad , Relación Estructura-Actividad , Tiadiazoles/sangre , Tiadiazoles/síntesis químicaRESUMEN
The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3 mg/kg.
Asunto(s)
Oxadiazoles/farmacología , Piperazinas/farmacología , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Femenino , Linfopenia/inducido químicamente , Linfopenia/patología , Estructura Molecular , Oxadiazoles/administración & dosificación , Oxadiazoles/química , Piperazinas/administración & dosificación , Piperazinas/química , Ratas , Ratas Endogámicas Lew , Receptores de Esfingosina-1-Fosfato , Relación Estructura-ActividadRESUMEN
Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Animales , Perros , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Haplorrinos , Humanos , Ratones , Microsomas/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Pirazoles/química , Piridinas/químicaRESUMEN
The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.
