RESUMEN
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Asunto(s)
Indoles/química , Indoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Cristalografía por Rayos X , Indazoles/química , Indazoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/química , Fosforilación , Relación Estructura-ActividadRESUMEN
A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Triazoles/química , Triazoles/farmacología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Modelos Moleculares , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Ratas , Relación Estructura-Actividad , Triazoles/síntesis químicaRESUMEN
The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Ciclopropanos/síntesis química , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Pirazinas/síntesis química , Pirroles/síntesis química , Administración Oral , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Células CACO-2 , Cristalografía por Rayos X , Ciclopropanos/farmacocinética , Ciclopropanos/farmacología , Técnicas de Silenciamiento del Gen , Ensayos Analíticos de Alto Rendimiento , Humanos , Interleucina-2/fisiología , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , Janus Quinasa 3/genética , Janus Quinasa 3/metabolismo , Ratones , Modelos Moleculares , Pirazinas/farmacocinética , Pirazinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , ARN Interferente Pequeño/genética , Ratas , Receptores de Interleucina-6/fisiología , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
The purinoceptor subtypes P2X(3) and P2X(2/3) have been shown to play a pivotal role in models of various pain conditions. Identification of a potent and selective dual P2X(3)/P2X(2/3) diaminopyrimidine antagonist RO-4 prompted subsequent optimization of the template. This paper describes the SAR and optimization of the diaminopyrimidine ring and particularly the substitution of the 2-amino group. The discovery of the highly potent and drug-like dual P2X(3)/P2X(2/3) antagonist RO-51 is presented.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Química Farmacéutica/métodos , Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2 , Pirimidinas/síntesis química , Pirimidinas/farmacología , Adenosina Trifosfato/química , Animales , Células CHO , Cricetinae , Cricetulus , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Receptores Purinérgicos P2/química , Relación Estructura-ActividadRESUMEN
P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X(3) and P2X(2/3) receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X(3)/P2X(2/3) antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X(3)/P2X(2/3) antagonist.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Química Farmacéutica/métodos , Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2 , Pirimidinas/síntesis química , Pirimidinas/farmacología , Adenosina Trifosfato/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Iones , Ligandos , Modelos Químicos , Receptores Purinérgicos P2/química , Relación Estructura-ActividadRESUMEN
Replacement of the N-butyl side-chain of lead 5-HT4 receptor antagonist 2 with propanesulfonylpiperidinyl, morpholinyl, and piperazinyl groups led to higher affinity analogs 4-6. In vitro drug metabolism screens and cassette pharmacokinetic studies in the dog led to identification of the N-methylpiperazinyl analog (6b), which displayed pharmacokinetic, selectivity, and safety parameters sufficient for advancement to the clinic for the treatment of urinary incontinence.