RESUMEN
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
GPR142 is a G protein-coupled receptor that is predominantly expressed in pancreatic ß-cells. GPR142 agonists stimulate insulin secretion in the presence of high glucose concentration, so that they could be novel insulin secretagogues with reduced or no risk of hypoglycemia. We report here the optimization of HTS hit compound 1 toward a proof of concept compound 33, which showed potent glucose lowering effects during an oral glucose tolerance test in mice and monkeys.
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
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
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
We have previously reported that optimization of a series of phenylacetic acid derivatives led to the discovery of CRTH2 and DP dual antagonists, such as AMG 009 and AMG 853. During the optimization process, we discovered that minor structural modifications also afforded potent and selective CRTH2 or DP antagonists. Here we report the structure-activity relationship that led to the discovery of selective CRTH2 antagonists such as 2 and 17, and selective DP antagonists, such as 4 and 5.
Asunto(s)
Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Asma/terapia , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Hipersensibilidad/tratamiento farmacológico , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Fenilacetatos/química , Fenilacetatos/farmacología , Prostaglandina D2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay. Compound 25 was identified as having the optimal balance of CXCR3 activity and pharmacokinetic properties across multiple pre-clinical species, which are reported herein.
Asunto(s)
Quinazolinas/síntesis química , Quinazolinonas/síntesis química , Receptores CXCR3/antagonistas & inhibidores , Animales , Bleomicina/toxicidad , Aberraciones Cromosómicas , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Inflamación , Concentración 50 Inhibidora , Leucocitos/efectos de los fármacos , Macaca fascicularis , Ratones , Modelos Químicos , Quinazolinas/farmacología , Quinazolinonas/farmacología , Factores de TiempoRESUMEN
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
A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties. These efforts led to selection of AMG 009 as a clinical candidate.
Asunto(s)
Asma/metabolismo , Receptores de Prostaglandina/química , Animales , Diseño de Fármacos , Humanos , Receptores de Prostaglandina/clasificación , Relación Estructura-Actividad , Células Th2/metabolismoRESUMEN
The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties. We will also discuss the efficacy of the lead compound 34 in a mouse model of cellular recruitment induced by bleomycin.
Asunto(s)
Antiinflamatorios/química , Pirimidinonas/química , Quinazolinonas/química , Receptores CXCR3/antagonistas & inhibidores , Sulfonas/química , Acetamidas/farmacología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Movimiento Celular , Perros , Haplorrinos , Humanos , Ratones , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Ratas , Receptores CXCR3/metabolismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/farmacologíaRESUMEN
A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo.
Asunto(s)
Compuestos Heterocíclicos/farmacología , Quinazolinonas/farmacología , Receptores CXCR3/antagonistas & inhibidores , Animales , Cromatografía Líquida de Alta Presión , Humanos , Quinazolinonas/farmacocinética , Ratas , EstereoisomerismoRESUMEN
A series of quinazolinone-derived inhibitors of the CXCR3 receptor have been synthesized and their affinity for the receptor evaluated. Compounds were evaluated in a (125)I-IP10 displacement assay and in in vitro cell migration assays to IP10, ITAC, and MIG using human peripheral blood mononuclear cells.