The substitution of alkoxy groups of enol ethers (1-methoxycyclohexenes, 1-methoxy-l-alkenes, and benzofuran) and aryl ethers (methoxynaphthalenes, cresyl methyl ethers, and dimethoxybenzenes) by hydrogen, alkyl groups, and aryl units, through Grignard reactions catalyzed by bis(triphenylphosphine)nickel dichloride or [1,3-bis-(diphenylphosphino)propane]nickel dichloride, is described. The stereochemistry of the new reaction is portrayed, especially in connection with processes involving ring opening of dihydropyrans and dihydrofurans. The reaction has been applied to the synthesis of a termite trail pheromone and the acetate of the Douglas fir beetle aggregation pheromone.
Accumulation of lipofuscin in the
retina is associated with pathogenesis
of atrophic age-related macular degeneration and Stargardt disease.
Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity.
Synthesis of lipofuscin bisretinoids depends on the influx of retinol
from serum to the retina. Compounds antagonizing the retinol-dependent
interaction of retinol-binding protein 4 (RBP4) with transthyretin
in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid
formation. We recently showed that A1120 (3), a potent
carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin
bisretinoid formation in the retinas of Abca4–/– mice. As part of the NIH
Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained
RBP4 antagonists with improved potency and metabolic stability. We
also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced
circulating plasma RBP4 protein levels by approximately 60%.
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