RESUMEN
The synthesis and pharmacological activity of a new series of pyrazoles that led to the identification of 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone (9k, EST64454) as a σ1 receptor (σ1R) antagonist clinical candidate for the treatment of pain are reported. The compound 9k is easily obtained through a five-step synthesis suitable for the production scale and shows an outstanding aqueous solubility, which together with its high permeability in Caco-2 cells will allow its classification as a BCS class I compound. It also shows high metabolic stability in all species, linked to an adequate pharmacokinetic profile in rodents, and antinociceptive properties in the capsaicin and partial sciatic nerve ligation models in mice.
Asunto(s)
Analgésicos/uso terapéutico , Dolor/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirazoles/uso terapéutico , Receptores sigma/antagonistas & inhibidores , Analgésicos/síntesis química , Analgésicos/farmacocinética , Animales , Células CACO-2 , Humanos , Ratones , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/farmacocinética , Pirazoles/síntesis química , Pirazoles/farmacocinética , Ratas Wistar , Relación Estructura-Actividad , Receptor Sigma-1RESUMEN
The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4-d]pyrimidine scaffold, led to highly active sigma-1 receptor (σ1R) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σ1R and the 4-(1-methylpyrazol-5-yl) derivative, 12f, was the most selective. Compound 12f is also one of the best σ1R ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile. In addition, 12f was identified as an antagonist of the σ1R in view of its potent antinociceptive profile in several pain models in mice.
RESUMEN
2,3,7-Trisubstituted indolizines were obtained from E- or Z-2-enynyl-4-substituted pyridines. The mechanistic pathway involves a base-catalyzed double-bond isomerization, if the E-isomer is the starting material, followed by a concerted pseudocoarctate cyclization.
Asunto(s)
Indolizinas/síntesis química , Piridinas/química , Catálisis , Ciclización , Indolizinas/química , Estructura Molecular , EstereoisomerismoRESUMEN
[chemical reaction: see text]. A stereoselective total synthesis of the visual pigment A2E has been achieved with use of palladium-catalyzed cross-coupling reactions in all key steps: a regioselective Suzuki or Negishi coupling of 2,4-dibromopyridine, a Sonogashira reaction, and a double Stille cross-coupling to complete the bispolyenyl skeleton.
