DP-155 is a
lipid prodrug of
indomethacin that comprises the latter conjugated to
lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by
phospholipase A2 (PLA)(2) to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons.
Indomethacin is the principal metabolite of
DP-155 in rat serum and, after
DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following
indomethacin administration. The brain to serum ratio was 3.5 times higher for
DP-155 than for
indomethacin. In vitro studies demonstrated that
DP-155 is a selective
cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its
indomethacin derivative nonselectively inhibits both COX-1 and -2.
DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its
indomethacin metabolite.
DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while
indomethacin caused
gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with
DP-155 compared to
indomethacin. In addition to reduced toxicity,
DP-155 had similar ameliorative effects to
indomethacin in
antipyretic and
analgesia models. Moreover,
DP-155 and
indomethacin were equally efficacious in reducing levels of
amyloid ss (Ass)42 in transgenic
Alzheimer's disease mouse (Tg2576) brains as well as reducing Ass42 intracellular uptake, neurodegeneration, and
inflammation in an in vitro AD model. The relatively high brain levels of
indomethacin after
DP-155 administration explain the equal efficacy of
DP-155 despite its low systemic blood concentrations. Compared to
indomethacin, the favored safety profile and equal efficacy of
DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for
analgesia.