RESUMEN

GPR119 is a 7-transmembrane receptor that is expressed in the enteroendocrine cells in the intestine and in the islets of Langerhans in the pancreas. Indolines and 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines were discovered as G protein-coupled receptor 119 (GPR119) agonists, and lead optimization efforts led to the identification of 1-methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)-1-piperidinecarboxylate (GSK1104252A) (3), a potent and selective GPR119 agonist. Compound 3 showed excellent pharmacokinetic properties and sufficient selectivity with in vivo studies supporting a role for GPR119 in glucose homeostasis in the rodent. Thus, 3 appeared to modulate the enteroinsular axis, improve glycemic control, and strengthen previous suggestions that GPR119 agonists may have utility in the treatment of type 2 diabetes.

Asunto(s)

Hipoglucemiantes/síntesis química , Piperidinas/síntesis química , Pirimidinas/síntesis química , Pirroles/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Línea Celular , Colon/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Incretinas/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piperidinas/farmacocinética , Piperidinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ERalpha and ERbeta binding affinity ranging from micromolar to low nanomolar.

Asunto(s)

Naftalenos/síntesis química , Naftalenos/farmacología , Receptores de Estrógenos/agonistas , Técnicas Químicas Combinatorias , Moduladores de los Receptores de Estrógeno/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Ligandos , Estructura Molecular , Naftalenos/química , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Relación Estructura-Actividad

RESUMEN

Modulation of estrogen action is an effective treatment for alleviating the symptoms associated with menopause, and also provides an alternative to ablative surgery for the treatment of breast cancer. The side effects associated with the currently used estrogen receptor-modulating drugs have resulted in the pursuit of agents with an improved therapeutic profile. Recent advances in understanding the molecular determinants of estrogen receptor signaling have contributed to the continued discovery and development of novel chemical compounds designed to exploit this knowledge. This review focuses on the recent clinical and preclinical development of novel classes of ligands that modulate the two estrogen receptor subtypes.

Asunto(s)

Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Humanos , Ligandos , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico

RESUMEN

Traditional approaches to discovery of selective estrogen receptor modulators (SERMs) have relied on ER binding and cell-based estrogen response element-driven assays to identify compounds that are osteoprotective but nonproliferative in breast and uterine tissues. To discover new classes of potential SERMs, we have employed a cell-free microsphere-based binding assay to rapidly characterize ERalpha interactions with conformation-sensing cofactor or phage display peptides. Peptide profiles of constrained triarenes were compared to known proliferative and nonproliferative ER ligands to discover potent quinoline-based ligands with minimal Ishikawa cell stimulation.

Asunto(s)

Quinolinas/síntesis química , Receptores de Estrógenos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Fosfatasa Alcalina/biosíntesis , Unión Competitiva , Línea Celular , Proliferación Celular/efectos de los fármacos , Sistema Libre de Células , Endometrio/citología , Inducción Enzimática , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/efectos de los fármacos , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Ligandos , Microesferas , Biblioteca de Péptidos , Quinolinas/química , Quinolinas/farmacología , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología

RESUMEN

A series of bis-aryl substituted guanidines have been discovered as potent NPY Y5 antagonists. The SAR and in vitro metabolic stability of these compounds are discussed.

Asunto(s)

Guanidinas/síntesis química , Guanidinas/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Guanidinas/química , Estructura Molecular , Ensayo de Unión Radioligante , Relación Estructura-Actividad

RESUMEN

The high-throughput manual solid-phase parallel synthesis of libraries comprising thousands of discrete samples using pellicular supports (i.e. SynPhase crowns and lanterns) and a suite of novel tools and techniques is described. Key aspects of this approach include the combination of a split-split-split synthesis strategy with spatial encoding to differentiate thousands of crowns, the rapid washing and filtration of up to 48 reaction vessels in parallel, the application of an inexpensive and environmentally friendly technique to remove trifluoroacetic acid from sixteen 96-well plates in parallel, and a high-throughput method for removing cleaved crowns from reusable pin racks. Tens of thousands of discrete samples have been produced in-house using this conceptually and operationally straightforward strategy.