RESUMEN
GPR142 is a novel GPCR that is predominantly expressed in pancreatic ß-cells. GPR142 agonists potentiate glucose-dependent insulin secretion, and therefore can reduce the risk of hypoglycemia. Optimization of our lead pyridinone-phenylalanine series led to a proof-of-concept compound 22, which showed in vivo efficacy in mice with dose-dependent increase in insulin secretion and a decrease in glucose levels.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Fenilalanina/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Glucemia/análisis , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Prueba de Tolerancia a la Glucosa , Células HEK293 , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Masculino , Ratones , Ratones Endogámicos , Microsomas/química , Fenilalanina/administración & dosificación , Fenilalanina/química , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., AM-2394). Structure-activity relationship studies are presented along with relevant pharmacokinetic and in vivo data.
RESUMEN
Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.
RESUMEN
Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.
RESUMEN
Herein, we report the lead optimization of amrinone-phenylalanine based GPR142 agonists. Structure-activity relationship studies led to the discovery of aminopyrazole-phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets.
RESUMEN
The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC(50) of 2.5 µM for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.
Asunto(s)
Factor 4E Eucariótico de Iniciación/metabolismo , Guanina/análogos & derivados , Guanosina Monofosfato/análogos & derivados , Guanosina Monofosfato/farmacología , Organofosfonatos/síntesis química , Caperuzas de ARN/metabolismo , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Factor 4E Eucariótico de Iniciación/química , Guanina/síntesis química , Guanina/farmacología , Guanosina Monofosfato/síntesis química , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Organofosfonatos/farmacología , Ácidos Fosforosos , Biosíntesis de Proteínas/efectos de los fármacos , Caperuzas de ARN/química , Conejos , Reticulocitos/efectos de los fármacos , Reticulocitos/metabolismo , Relación Estructura-ActividadRESUMEN
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
Asunto(s)
Antineoplásicos/síntesis química , Benzazepinas/síntesis química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Lactamas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Tionas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzazepinas/farmacocinética , Benzazepinas/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactamas/farmacocinética , Lactamas/farmacología , Ratones , Ratones Desnudos , Mitosis , Modelos Moleculares , Trasplante de Neoplasias , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tionas/farmacocinética , Tionas/farmacología , Trasplante Heterólogo , Quinasa Tipo Polo 1RESUMEN
Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2. These efforts led to the discovery of AMG 853 (2-(4-(4-(tert-butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenyl sulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid), which is being evaluated in human clinical trials for asthma.
RESUMEN
Several potent, functionally active MCHr1 antagonists derived from quinolin-2(1H)-ones and quinazoline-2(1H)-ones have been synthesized and evaluated. Pyridylmethyl substitution at the quinolone 1-position results in derivatives with low-nM binding potency and good selectivity with respect to hERG binding.
Asunto(s)
Quinazolinas/química , Quinazolinas/farmacología , Quinolonas/química , Quinolonas/farmacología , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Ratones , Quinazolinas/farmacocinética , Quinolonas/farmacocinéticaRESUMEN
The identification of a novel series of benzamide-containing MCHr1 antagonists is described. Compound 22 displayed moderate efficacy in a diet induced obesity mice model.
Asunto(s)
Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Benzamidas/química , Benzamidas/farmacología , Piperidinas/química , Piperidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/síntesis química , Benzamidas/síntesis química , Unión Competitiva , Modelos Animales de Enfermedad , Perros , Ratones , Estructura Molecular , Piperidinas/síntesis química , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Factores de TiempoRESUMEN
Several potent and efficacious MCHr1 antagonists containing an ortho-amino benzamide or nicotinamide chemotype have been identified, exemplified by 28 and 50.