57524-13-7

A method of treating an ocular disorder in a subject associated with increased all-trans-retinal in an ocular tissue includes administering to the subject a therapeutically effective amount of a primary amine compound of formula (I); and pharmaceutically acceptable salts thereof.

All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.

The all-E isomer of (4,4'-13C2)astaxanthin (1a) has been prepared by total synthesis starting from commercially available 99% 13C enriched acetonitrile. The labelled astaxanthin was obtained in high purity and with high isotope incorporation. For this synthesis, the C15 + C10 + C15 strategy was used. The central C10-synthon, 2,7-dimethylocta-2,4,6-triene- 1,8-dial (3), was coupled with 13C-enriched C15-phosphonium salt 2a. The new synthetic scheme for the preparation of the C15-phosphonium salt is discussed in this paper; the same scheme can be used to label all positions and combinations of positions of the C15-phosphonium salt.

The effect of complexation of terpene compounds with cyclodextrins on photolysis depends on the type of cyclodextrin and on the structure of the initial substrates. In some cases, only a change in the reaction rate is observed; in other cases, the complexation results in allylic rearrangements, hydride and acyl shifts, and cyclization with the formation of four-, five-, and six-membered cycles, whereas only cis-trans isomerization reactions are observed in the absence of complexation.

Thujone, a waste by-product of the Canadian forest industry, has been utilized as a starting material to develop a versatile synthetic route to the damascones (rose oil ketones) and related analogues.The synthetic sequence provides a route to β-cyclocitral (45), the latter having been previously converted to β-damascone (2).In addition, thujone-drived intermediates are converted to β-damascenone (48) and to intermediates that can be utilized for the preparation of damascone analogues.In conjunction with the above, an efficient route to safronitrile (42), β-cyclogeranonitrile (43), and β-cyclocitral (45) from 2,6-dimethylcyclohexanone has been developed.In summary, these studies afford an attractive versatile route to these important perfumery materials.