[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.
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.
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.
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