RESUMEN
Despite the extensive literature describing the role of the ATP-gated P2X(3) receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X(3) antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85.
Asunto(s)
Descubrimiento de Drogas/métodos , Antagonistas del Receptor Purinérgico P2 , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacología , Tiofenos/química , Tiofenos/metabolismo , Tiofenos/farmacología , Animales , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Unión Proteica/fisiología , Ratas , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X3 , Relación Estructura-ActividadRESUMEN
A variety of novel aminoheterocycle scaffolds as selective monoamine reuptake inhibitors have been prepared and one of these scaffolds is achiral. The main elements responsible for hERG channel, CYP2D6 and CYP3A4 inhibition were identified.
Asunto(s)
Inhibidores del Citocromo P-450 CYP2D6 , Inhibidores del Citocromo P-450 CYP3A , Compuestos Heterocíclicos/química , Inhibidores de la Captación de Neurotransmisores/química , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Humanos , Microsomas Hepáticos/metabolismo , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacologíaRESUMEN
A series of 3,3-disubstituted pyrrolidine monoamine triple reuptake inhibitors were discovered. Analogues with low nanomolar potency, good human in vitro microsomal stability and in vitro permeability, and low drug-drug interaction potential are described. One example showed in vivo anti-depressant-like effects in the mouse tail suspension assay with a minimum effective dose of 30 mg/kg i.p.
Asunto(s)
Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Antidepresivos/farmacología , Inhibidores de Captación de Dopamina/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Pirrolidinas/química , Serotonina/metabolismo , Cola (estructura animal)/efectos de los fármacosRESUMEN
A four step synthesis of 4(S)-oxazolidineacetic acid, 2-oxo benzyl ester (D-Oxac-OBn) from L-Asp-OH in 45% overall yield is reported. The formation of by-products is completely avoided, by microwave irradiation and by the use of caesium carbonate as base. Moreover the synthesis and IR and 1H NMR conformational analysis of the tetramers Boc-L-Val-D-Oxac-L-Ala-OBn and Boc-L-Val-D-Oxac-Aib-L-Ala-OBn in solution is reported.