RESUMEN
Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.
Asunto(s)
Benzamidas/síntesis química , Guanidinas/síntesis química , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Animales , Benzamidas/química , Benzamidas/farmacología , Disponibilidad Biológica , Plaquetas/citología , Plaquetas/efectos de los fármacos , Línea Celular , Permeabilidad de la Membrana Celular , Tamaño de la Célula , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Guanidinas/química , Guanidinas/farmacología , Humanos , Masculino , Membranas Artificiales , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Permeabilidad , Isoformas de Proteínas/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Intercambiador 1 de Sodio-Hidrógeno , Relación Estructura-ActividadRESUMEN
A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability.
Asunto(s)
Azepinas/química , Receptor Cannabinoide CB2/agonistas , Azepinas/farmacología , Células CACO-2 , Permeabilidad de la Membrana Celular , Ensayos Analíticos de Alto Rendimiento , Humanos , Microsomas Hepáticos/metabolismo , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
Two closely related scaffolds were identified through an uHTS campaign as desirable starting points for the development of Rho-Kinase (ROCK) inhibitors. Here, we describe our hit-to-lead evaluation process which culminated in the rapid discovery of potent leads such as 22 which successfully demonstrated an early in vivo proof of concept for anti-hypertensive activity.
Asunto(s)
Isoquinolinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Descubrimiento de Drogas , Isoquinolinas/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , RatasRESUMEN
A highly selective series of bisbenzamide inhibitors of Rho-associated coiled-coil forming protein kinase (ROCK) and a related ureidobenzamide series, both identified by high throughput screening (HTS), are described. Details of the hit validation and lead generation process, including structure-activity relationship (SAR) studies, a selectivity assessment, target-independent profiling (TIP) results, and an analysis of functional activity using a rat aortic ring assay are discussed.
Asunto(s)
Bisbenzimidazol/química , Inhibidores de Proteínas Quinasas/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Aorta/enzimología , Bisbenzimidazol/farmacología , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Concentración 50 Inhibidora , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Relación Estructura-Actividad , Urea/químicaRESUMEN
A series of novel 5-aminomethyl-1H-benzimidazole based inhibitors of Itk were prepared. Structure-activity relationships, selectivity and cell activity are reported for this series. Compound 2, a potent and selective antagonist of Itk, inhibited anti-CD3 antibody induced IL-2 production in vivo in mice.
Asunto(s)
Bencimidazoles/administración & dosificación , Bencimidazoles/química , Bencimidazoles/síntesis química , Química Farmacéutica/métodos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Administración Oral , Animales , Bencimidazoles/farmacología , Complejo CD3/biosíntesis , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Modelos Químicos , Relación Estructura-Actividad , Linfocitos T/citologíaRESUMEN
We have identified two novel MEK5 inhibitors, BIX02188 and BIX02189, which inhibited catalytic function of purified, MEK5 enzyme. The MEK5 inhibitors blocked phosphorylation of ERK5, without affecting phosphorylation of ERK1/2 in sorbitol-stimulated HeLa cells. The compounds also inhibited transcriptional activation of MEF2C, a downstream substrate of the MEK5/ERK5 signaling cascade, in a cellular trans-reporter assay system. These inhibitors offer novel pharmacological tools to better characterize the role of the MEK5/ERK5 pathway in various biological systems.
Asunto(s)
Compuestos de Anilina/farmacología , Indoles/farmacología , MAP Quinasa Quinasa 5/antagonistas & inhibidores , Proteína Quinasa 7 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Compuestos de Anilina/aislamiento & purificación , Células HeLa , Humanos , Indoles/aislamiento & purificación , Proteínas de Dominio MADS/antagonistas & inhibidores , Proteínas de Dominio MADS/genética , MAP Quinasa Quinasa 5/metabolismo , Factores de Transcripción MEF2 , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Factores Reguladores Miogénicos/antagonistas & inhibidores , Factores Reguladores Miogénicos/genética , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/aislamiento & purificación , Sorbitol/farmacología , Activación Transcripcional/efectos de los fármacosRESUMEN
Previously, we reported a series of novel benzimidazole based Itk inhibitors that exhibited excellent enzymatic potency and selectivity but low microsomal stability. Employing a structure based approach a new series of inhibitors with comparable potency and selectivity to the original series and with a potential for improved microsome stability was identified.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/síntesis química , Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Microsomas Hepáticos/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Adenosina Trifosfato/química , Administración Oral , Sitios de Unión , Complejo CD3/química , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Microsomas Hepáticos/química , Relación Estructura-Actividad , Linfocitos T/metabolismoRESUMEN
We have recently reported the discovery of a novel class of glucocorticoid receptor (GR) antagonists, exemplified by 3, containing a 1,2-dihydroquinoline molecular scaffold. Further SAR studies of these antagonists uncovered chemical modifications conveying agonist functional activity to this series. These agonists exhibit good GR binding affinity and are selective against other nuclear hormone receptors.
Asunto(s)
Quinolinas/química , Quinolinas/farmacología , Receptores de Glucocorticoides/agonistas , Quinolinas/metabolismo , Receptores de Glucocorticoides/metabolismo , Relación Estructura-ActividadRESUMEN
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/enzimología , Linfocitos T CD4-Positivos/inmunología , Humanos , Interleucina-2/metabolismo , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Proteína Quinasa C-theta , Relación Estructura-ActividadRESUMEN
High-throughput screening is routinely employed as a method for the identification of novel hit structures. Large numbers of active compounds are typically procured in this way and must undergo a rigorous validation process. This process is described in detail for a collection of screening hits identified as inhibitors of IkappaB kinase-beta (IKKbeta), a key regulatory enzyme in the nuclear factor-kappaB (NF-kappaB) pathway. From these studies, a promising hit series was selected. Subsequent lead generation activities included the development of a pharmacophore hypothesis and structure-activity relationship (SAR) for the hit series. This led to the exploration of related scaffolds offering additional opportunities, and the various structural classes were comparatively evaluated for enzyme inhibition, selectivity, and drug-like properties. A novel lead series of thienopyridines was thereby established, and this series advanced into lead optimization for further development.