RESUMEN
In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.
Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1 , Piridonas , Conformación Molecular , Piridonas/farmacología , Relación Estructura-ActividadRESUMEN
In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.
Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/metabolismo , Quinazolinas/química , Aldehído Oxidasa/metabolismo , Animales , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Estabilidad de Medicamentos , Semivida , Hepatocitos/metabolismo , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Ratones , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/metabolismo , Quinazolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.
Asunto(s)
Aminas/química , Aminas/farmacología , Diseño de Fármacos , Pirazoles/química , Pirazoles/farmacología , Receptores AMPA/metabolismo , Regulación Alostérica , Aminas/síntesis química , Aminas/farmacocinética , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Pirazoles/síntesis química , Pirazoles/farmacocinética , Ratas , Ratas Wistar , Receptores AMPA/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
Asunto(s)
Indazoles/química , Receptores AMPA/química , Tiofenos/química , Regulación Alostérica , Animales , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Indazoles/síntesis química , Indazoles/farmacología , Microsomas/metabolismo , Estructura Terciaria de Proteína , Ratas , Receptores AMPA/metabolismo , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
In this article, we report our investigation of a phenomenon by which bridging morpholines across the ring with one-carbon tethers leads to a counterintuitive reduction in lipophilicity. This effect was also found to occur in piperazines and piperidines and lowered the measured log D7.4 of the bridged molecules by as much as -0.8 relative to their unbridged counterparts. As lowering lipophilicity without introducing additional heteroatoms can be desirable, we believe this potentially provides a useful tactic to improve the drug-like properties of molecules containing morpholine-, piperazine-, and piperidine-like motifs.
Asunto(s)
Carbono/química , Interacciones Hidrofóbicas e Hidrofílicas , Morfolinas/química , Piperazinas/química , Piperidinas/química , Modelos Moleculares , Estructura MolecularRESUMEN
A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.