RESUMEN
Autoimmune diseases affect 50 million Americans, predominantly women, and are thought to be one of the top 10 leading causes of death among women in age groups up to 65 years. A central role for TH17 cells has been highlighted by genome-wide association studies (GWAS) linking genes preferentially expressed in TH17 cells to several human autoimmune diseases. We and others have reported that the nuclear receptors REV-ERBα and ß are cell-intrinsic repressors of TH17 cell development and pathogenicity and might therefore be therapeutic targets for intervention. Herein, we describe detailed SAR studies of a novel REV-ERBα-selective scaffold. Metabolic stability of the ligands was optimized allowing for in vivo interrogation of the receptor in a mouse model of multiple sclerosis (EAE) with a ligand (34). Reduction in frequency and number of T-cells in the CNS as well as key REV-ERB target genes is a measure of target engagement in vivo.
Asunto(s)
Estudio de Asociación del Genoma Completo , Esclerosis Múltiple , Ratones , Animales , Humanos , Femenino , Masculino , Factores de Transcripción/genética , Diferenciación Celular , Esclerosis Múltiple/tratamiento farmacológico , Relación Estructura-Actividad , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/agonistas , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismoRESUMEN
The discovery and initial optimization of a series of phenylalanine based agonists for GPR142 is described. The structure-activity-relationship around the major areas of the molecule was explored to give agonists 90 times more potent than the initial HTS hit in a human GPR142 inositol phosphate accumulation assay. Removal of CYP inhibition by exploration of the pyridine A-ring is also described.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Fenilalanina/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Relación Dosis-Respuesta a Droga , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Fenilalanina/síntesis química , Fenilalanina/química , Ratas , Relación Estructura-ActividadRESUMEN
A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties.
Asunto(s)
Benzodiazepinas/química , Benzodiazepinas/farmacología , Receptores de Ghrelina/antagonistas & inhibidores , Receptores de Ghrelina/metabolismo , Animales , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacocinética , Calcio/metabolismo , Línea Celular , Hepatocitos/metabolismo , Humanos , Mediciones Luminiscentes , Obesidad/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
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
Previous efforts have led to the identification of a potent, selective, and nonphlorizin based SGLT2 inhibitor 1. This Letter describes efforts to further optimize the potency, microsomal stability, solubility and pharmacokinetic properties of this series of SGLT2 inhibitors. From these efforts, compounds 28 and 32 have improved solubility and pharmacokinetic properties compared to compound 1.
Asunto(s)
Triazoles/síntesis química , Estabilidad de Medicamentos , Estructura Molecular , Florizina/química , Solubilidad , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
Piperazine-bisamide analogs were discovered as partial agonists of human growth hormone secretagogue receptor (GHSR) in a high throughput screen. The partial agonists were optimized for potency and converted into antagonists through structure-activity relationship (SAR) studies. The efforts also led to the identification of potent antagonist with favorable PK profile suitable as a tool compound for in vivo studies.
Asunto(s)
Amidas/química , Fármacos Antiobesidad/química , Indoles/química , Piperazinas/química , Receptores de Ghrelina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/uso terapéutico , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/uso terapéutico , Ensayos Analíticos de Alto Rendimiento , Humanos , Indoles/síntesis química , Indoles/uso terapéutico , Obesidad/tratamiento farmacológico , Piperazinas/síntesis química , Piperazinas/uso terapéutico , Ratas , Receptores de Ghrelina/metabolismo , Relación Estructura-ActividadRESUMEN
Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Fenilacetatos/química , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Estabilidad de Medicamentos , Femenino , Humanos , Enlace de Hidrógeno , Ratones Desnudos , Mieloma Múltiple/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.
Asunto(s)
Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Inhibidores Enzimáticos/química , Humanos , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/antagonistas & inhibidoresRESUMEN
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
The design and parallel synthesis of potent, small molecule partial agonists of Neuromedin B receptor based on the 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide core is described.
Asunto(s)
Química Farmacéutica/métodos , Indoles/química , Receptores de Bombesina/agonistas , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Indoles/farmacología , Relación Estructura-ActividadRESUMEN
Low levels of transfection efficacy and lipid-associated cytotoxicity have complicated the use of cationic lipids to facilitate transfer of exogenous DNA to eukaryotic cells. To address these issues, we synthesized a panel of six tetraester polyamines that were designed to minimize cytotoxicity by using pentaerythritol to link the hydrophobic and the DNA-binding domains. We conducted this study to probe the effects of structural modifications around pentaerythritol as a linker on transfection activity and cell viability. We compared polyamines against commercial lipid reagents using luciferase and green fluorescent protein transfection assays in both CHO and NIH3T3 cells. Measurement of transfection activity and cytotoxicity using flow cytometry showed that the more active polyamine analogs exhibited activities comparable to LipofectAMINE PLUS and TransFast. Flow cytometry analyses revealed that all the pentaerythritol-based polyamines were uniformly nontoxic, whereas transfection activity was dependent on headgroup and sidechain composition. These results demonstrate that pentaerythritol is a useful core material for the development of active, nontoxic transfection agents.