RESUMEN
In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compounds have not been described. We are hereby reporting a series of novel 3-(pyrazol-4-yl) imidazolidine-2,4-diones as potent and selective TAS2R8 antagonists. In human sensory tests, S6821 and S7958, two of the most potent analogues from the series, demonstrated efficacy in blocking TAS2R8-mediated bitterness and were selected for development. Following data evaluation by expert panels of a number of national and multinational regulatory bodies, including the US, the EU, and Japan, S6821 and S7958 were approved as safe under conditions of intended use as bitter taste blockers.
Asunto(s)
Hidantoínas/farmacología , Pirazoles/farmacología , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Gusto/efectos de los fármacos , Animales , Café/química , Descubrimiento de Drogas , Estabilidad de Medicamentos , Humanos , Hidantoínas/síntesis química , Hidantoínas/toxicidad , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/toxicidad , Ratas , Relación Estructura-ActividadRESUMEN
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
Asunto(s)
Inhibidores del Citocromo P-450 CYP2D6 , Indanos/síntesis química , Indanos/farmacología , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/antagonistas & inhibidores , Clorhidrato de Atomoxetina , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Indanos/química , Concentración 50 Inhibidora , Microsomas Hepáticos/metabolismo , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/química , Propilaminas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/síntesis química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/farmacología , Aminas/química , Clorhidrato de Atomoxetina , Sitios de Unión , Línea Celular , Química Farmacéutica/métodos , Desipramina/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Propilaminas/química , Relación Estructura-ActividadRESUMEN
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
Asunto(s)
Pirrolidinas/química , Pirrolidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Concentración 50 Inhibidora , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/química , Urea/farmacocinética , Urea/farmacologíaRESUMEN
A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
Asunto(s)
Química Farmacéutica/métodos , Cromonas/síntesis química , Melaninas/química , Quinolonas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de la Hormona Hipofisaria/química , Administración Oral , Animales , Cromonas/química , Diseño de Fármacos , Humanos , Microsomas Hepáticos/metabolismo , Modelos Químicos , Quinolonas/química , Ratas , Factores de TiempoRESUMEN
A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.