RESUMEN
A potent series of substituted (2S,4S)-benzylproline α(2)δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-L-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development.
Asunto(s)
Diseño de Fármacos , Prolina/química , Prolina/síntesis química , Animales , Humanos , Concentración 50 Inhibidora , Ligandos , Estructura Molecular , Dolor , Prolina/farmacología , Ratas , PorcinosRESUMEN
Conformational constraint has been used to design a potent series of α(2)δ ligands derived from the readily available starting material (2S,4R)-hydroxy-l-proline. The ligands have improved physicochemistry and potency compared to their linear counterparts (described in our earlier publication) and the lead compound has been progressed to clinical development.
Asunto(s)
Diseño de Fármacos , Hidroxiprolina/síntesis química , Aminas/química , Aminas/farmacocinética , Animales , Células Cultivadas , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Perros , Gabapentina , Humanos , Hidroxiprolina/química , Ligandos , Estructura Molecular , Subunidades de Proteína/química , Ratas , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
A new series of glycine-derived ligands of the α(2)δ subunit of voltage gated calcium channels is described. Several novel compounds (7) based on (6) were prepared that possessed a potency <100 nM in the α(2)δ binding assay.
Asunto(s)
Canales de Calcio/efectos de los fármacos , Glicina/síntesis química , Ligandos , Alquilación , Glicina/química , Glicina/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Subunidades de Proteína/química , Relación Estructura-ActividadRESUMEN
Synthesis of a number of bicyclic five-membered ring derivatives of gabapentin led to the identification of two compounds, (-)-(11A) and (20A) which both had an excellent level of potency against alpha(2)delta and were profiled in an in vivo model of neuropathic pain.