RESUMEN
We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK-GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%).
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Diabetes Mellitus/tratamiento farmacológico , Glucoquinasa/antagonistas & inhibidores , Hepatocitos/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Piperazinas/química , Sulfonamidas/farmacología , Animales , Disponibilidad Biológica , Glucemia/metabolismo , Proteínas Portadoras/metabolismo , Cristalografía por Rayos X , Diabetes Mellitus/metabolismo , Modelos Animales de Enfermedad , Glucoquinasa/metabolismo , Hepatocitos/metabolismo , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperazinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.
Asunto(s)
Proteínas Portadoras/metabolismo , Glucoquinasa/metabolismo , Hipoglucemiantes/química , Piperazinas/química , Animales , Sitios de Unión , Proteínas Portadoras/química , Cristalografía por Rayos X , Glucoquinasa/química , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Piperazinas/efectos adversos , Piperazinas/farmacología , Conformación Proteica , Transporte de Proteínas , Ratas , Ratas Zucker , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/efectos adversos , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.
Asunto(s)
Proteínas Portadoras/metabolismo , Glucoquinasa/metabolismo , Hipoglucemiantes/química , Piperazinas/síntesis química , Sulfonamidas/síntesis química , Alquinos/síntesis química , Alquinos/farmacocinética , Alquinos/farmacología , Animales , Glucemia/metabolismo , Proteínas Portadoras/química , Glucoquinasa/química , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Morfolinas/síntesis química , Morfolinas/farmacocinética , Morfolinas/farmacología , Piperazinas/farmacocinética , Piperazinas/farmacología , Unión Proteica , Transporte de Proteínas , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.
Asunto(s)
Hiperparatiroidismo Secundario/tratamiento farmacológico , Tiazoles/química , Tiazoles/uso terapéutico , Urea/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Semivida , Hiperparatiroidismo Secundario/metabolismo , Hiperparatiroidismo Secundario/patología , Masculino , Hormona Paratiroidea/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/química , Receptores Sensibles al Calcio/metabolismo , Tiazoles/farmacocinéticaRESUMEN
Through the analysis of X-ray crystallographic information and previous SAR studies, a novel series of protein kinase B (PKB/AKT) inhibitors was developed. The compounds showed nanomolar inhibition of AKT1 and were selective against cyclin-dependent kinase 2 (CDK2).
Asunto(s)
Amidas/farmacología , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Técnicas de Química Sintética , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Modelos Moleculares , Estructura Molecular , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.
Asunto(s)
Bencilaminas/química , Bencilaminas/farmacología , Hormona Paratiroidea/antagonistas & inhibidores , Hormona Paratiroidea/sangre , Receptores Sensibles al Calcio/metabolismo , Administración Oral , Animales , Bencilaminas/administración & dosificación , Bencilaminas/farmacocinética , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Our efforts to discover potent, orally bioavailable type II calcimimetic agents for the treatment of secondary hyperparathyroidism focused on the development of ring constrained analogues of the known calcimimetic R-568. The structure-activity relationships of various substituted heterocycles and their effects on the human calcium-sensing receptor are discussed. Pyrazole 15 was shown to be efficacious in a rat in vivo pharmacodynamic model.
Asunto(s)
Compuestos de Anilina/síntesis química , Metilaminas/síntesis química , Pirazoles/síntesis química , Receptores Sensibles al Calcio/agonistas , Administración Oral , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Disponibilidad Biológica , Línea Celular , Cristalografía por Rayos X , Humanos , Hiperparatiroidismo Secundario/tratamiento farmacológico , Masculino , Metilaminas/química , Metilaminas/farmacología , Estructura Molecular , Hormona Paratiroidea/sangre , Fenetilaminas , Propilaminas , Pirazoles/química , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel route to functionalized carbazoles utilizing a tandem Suzuki cross-coupling/SNAr protocol is described. This process was found to be compatible with a variety of electron-withdrawing groups including aldehydes, esters, and sulfones. Using this method, a concise total synthesis (four steps, 50% overall yield) of the carbazole alkaloid glycosinine was achieved.
Asunto(s)
Argón/química , Carbazoles/química , Reactivos de Enlaces Cruzados/química , Azufre/química , Modelos Moleculares , Conformación Molecular , Estructura MolecularRESUMEN
Structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/farmacología , Nitrilos/química , Nitrilos/farmacología , Piridinas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tetrazoles/química , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Antagonistas de Aminoácidos Excitadores/química , Cinética , Ratones , Estructura Molecular , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Sensibilidad y Especificidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Interest in water soluble COX-2 inhibitors that can be administered intravenously led to the development of novel pro-drugs of a furanone based COX-2 inhibitor 2. Transforming the lactone moiety of the furanone to an imidate or an ortho-ester with a hydrophilic, endogenous appendage resulted in water soluble pro-drugs that converted to the parent drug in vivo.
Asunto(s)
Inhibidores de la Ciclooxigenasa/síntesis química , Lactonas/síntesis química , Profármacos/síntesis química , Prostaglandina-Endoperóxido Sintasas/metabolismo , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Ésteres , Furanos , Imidas , Indicadores y Reactivos , Lactonas/química , Lactonas/farmacología , Modelos Moleculares , Estructura Molecular , Profármacos/química , Profármacos/farmacología , SolubilidadRESUMEN
Structure-activity relationship studies on 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery of 2-(2-[3-(pyridin-3-yloxy)phenyl]-2H-tetrazol-5-yl)pyridine (10)-a highly potent and selective mGlu5 receptor antagonist with good brain penetration and in vivo receptor occupancy in rat and cross-species oral bioavailability.
Asunto(s)
Ansiolíticos/farmacocinética , Nitrilos/farmacocinética , Piridinas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tetrazoles/química , Tetrazoles/farmacocinética , Administración Oral , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/química , Disponibilidad Biológica , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Estructura Molecular , Nitrilos/química , Piridinas/farmacocinética , Ratas , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
Structure-activity relationship studies performed around 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile for the purpose of developing novel mGlu5 receptor antagonists are described. Synthesis of a series of four-ring tetrazoles led to the discovery of 3-[3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine, a highly potent, brain penetrant, azole-based mGlu5 receptor antagonist.
Asunto(s)
Ansiolíticos/farmacocinética , Nitrilos/síntesis química , Piridinas/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tetrazoles/síntesis química , Administración Oral , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/síntesis química , Disponibilidad Biológica , Estructura Molecular , Nitrilos/química , Nitrilos/farmacocinética , Piridinas/química , Piridinas/farmacocinética , Ratas , Receptor del Glutamato Metabotropico 5 , Relación Estructura-Actividad , Tetrazoles/química , Tetrazoles/farmacocinéticaRESUMEN
Structure-activity relationship studies focused on bio-isosteric replacements of 2-pyridyl resulted in mGlu5 receptor antagonists with reduced inhibition of cytochrome P450 1A2. This led to highly potent, selective and orally bioavailable 2-imidazolyl tetrazoles such as (10) that are devoid of cytochrome P450 inhibitory activity.