RESUMEN
Structure-guided progression of a purine-derived series of TNNI3K inhibitors directed design efforts that produced a novel series of 4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif. Herein, we report a detailed understanding of the intrinsic conformational preferences of the scaffold, which impart high specificity for TNNI3K. Further manipulation of the template based on the conformational analysis and additional structure-activity relationship studies provided enhancements in kinase selectivity and pharmacokinetics that furnished an advanced series of potent inhibitors. The optimized compounds (e.g., GSK854) are suitable leads for identifying new cardiac medicines and have been employed as in vivo tools in investigational studies aimed at defining the role of TNNI3K within heart failure.
Asunto(s)
Cardiotónicos/síntesis química , Cardiotónicos/farmacología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Disponibilidad Biológica , Cardiotónicos/farmacocinética , Biología Computacional , Diseño de Fármacos , Receptores ErbB/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Modelos Moleculares , Conformación Molecular , Proteínas Serina-Treonina Quinasas , Pirimidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Investigation of troponin I-interacting kinase (TNNI3K) as a potential target for the treatment of heart failure has produced a series of substituted N-methyl-3-(pyrimidin-4-ylamino)benzenesulfonamide inhibitors that display excellent potency and selectivity against a broad spectrum of protein kinases. Crystal structures of prototypical members bound to the ATP-binding site of TNNI3K reveal two anchoring hydrogen bond contacts: (1) from the hinge region amide N-H to the pyrimidine nitrogen and (2) from the sulfonamide N-H to the gatekeeper threonine. Evaluation of various para-substituted benzenesulfonamides defined a substituent effect on binding affinity resulting from modulation of the sulfonamide H-bond donor strength. An opposite electronic effect emerged for the hinge NH-pyrimidine H-bond interaction, which is further illuminated in the correlation of calculated H-bond acceptor strength and TNNI3K affinity for a variety of hinge binding heterocycles. These fundamental correlations on drug-receptor H-bond interactions may be generally useful tools for the optimization of potency and selectivity in the design of kinase inhibitors.
Asunto(s)
Diseño de Fármacos , Quinasas Quinasa Quinasa PAM/química , Inhibidores de Proteínas Quinasas/química , Relación Dosis-Respuesta a Droga , Humanos , Enlace de Hidrógeno , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas , Relación Estructura-ActividadRESUMEN
A series of selective TNNI3K inhibitors were developed by modifying the hinge-binding heterocycle of a previously reported dual TNNI3K/B-Raf inhibitor. The resulting quinazoline-containing compounds exhibit a large preference (up to 250-fold) for binding to TNNI3K versus B-Raf, are useful probes for elucidating the biological pathways associated with TNNI3K, and are leads for discovering novel cardiac medicines. GSK114 emerged as a leading inhibitor, displaying significant bias (40-fold) for TNNI3K over B-Raf, exceptional broad spectrum kinase selectivity, and adequate oral exposure to enable its use in cellular and in vivo studies.
Asunto(s)
Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Sulfonamidas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Quinasas Quinasa Quinasa PAM/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in in vitro and in vivo experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines.
Asunto(s)
Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Purinas/química , Administración Oral , Animales , Línea Celular , Cristalografía por Rayos X , Humanos , Masculino , Unión Proteica , Conformación Proteica , Proteínas Serina-Treonina Quinasas , Purinas/farmacocinética , Purinas/farmacología , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
Percutaneous coronary intervention is first-line therapy for acute coronary syndromes (ACS) but can promote cardiomyocyte death and cardiac dysfunction via reperfusion injury, a phenomenon driven in large part by oxidative stress. Therapies to limit this progression have proven elusive, with no major classes of new agents since the development of anti-platelets/anti-thrombotics. We report that cardiac troponin I-interacting kinase (TNNI3K), a cardiomyocyte-specific kinase, promotes ischemia/reperfusion injury, oxidative stress, and myocyte death. TNNI3K-mediated injury occurs through increased mitochondrial superoxide production and impaired mitochondrial function and is largely dependent on p38 mitogen-activated protein kinase (MAPK) activation. We developed a series of small-molecule TNNI3K inhibitors that reduce mitochondrial-derived superoxide generation, p38 activation, and infarct size when delivered at reperfusion to mimic clinical intervention. TNNI3K inhibition also preserves cardiac function and limits chronic adverse remodeling. Our findings demonstrate that TNNI3K modulates reperfusion injury in the ischemic heart and is a tractable therapeutic target for ACS. Pharmacologic TNNI3K inhibition would be cardiac-selective, preventing potential adverse effects of systemic kinase inhibition.
Asunto(s)
Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Isquemia Miocárdica/enzimología , Isquemia Miocárdica/fisiopatología , Estrés Oxidativo , Proteínas Quinasas/metabolismo , Remodelación Ventricular , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/enzimología , Síndrome Coronario Agudo/patología , Síndrome Coronario Agudo/fisiopatología , Animales , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Eliminación de Gen , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/fisiopatología , Humanos , Quinasas Quinasa Quinasa PAM/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/patología , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Superóxidos/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/enzimología , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología , Remodelación Ventricular/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Optimisation of a series of biaryl sulphonamides resulted in the identification of compound 14 [corrected] which demonstrated dose-dependent and strain-specific inhibition of monocyte recruitment in a thioglycollate-induced peritonitis model of inflammation. [Formula: see text]. [corrected].
Asunto(s)
Azoles/química , Receptores CCR2/antagonistas & inhibidores , Sulfonamidas/química , Administración Oral , Animales , Azoles/síntesis química , Azoles/farmacocinética , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Semivida , Unión Proteica , Ratas , Receptores CCR2/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pK(a), yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma.
Asunto(s)
Receptores CCR2/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Estructura Molecular , Receptores CCR1/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.