Abstract 585: A Novel LXR Ligand Reduces LDL Cholesterol in Monkey
LXRs act as a transcriptional master switch for coordinate regulation of gene expression involved in cellular cholesterol homeostasis encompassing cholesterol transport, catabolism and absorption. WAY-252623 is a recently developed small molecule modulator of LXR. In the current studies, WAY-252623 was profiled in cynomolgous monkeys for effects on serum cholesterol, TG, lipoproteins and liver enzymes (ALT and AST) as well as LXR target genes (ABCA1 and ABCG1) in whole blood. Study duration was 28 days and blood samples were obtained for analysis at predose (day 0) and 2 hr following administration of WAY-252623 (15 and 50 mg/kg/day by gavage) on days 7, 14, 21 and 28. In the monkeys, WAY-252623 caused significant reductions in serum total (50–55%) and LDL-cholesterol (70 –77%) in a time- and dose-dependent manner. Decreases in LDL-c were noted as early as 7d reaching a maximum by 28d. Significantly, WAY-253623 reduced lipid levels more than simvastatin (20 mg/kg/day, Study II) alone. No additive effect was demonstrated with combined treatment (simvastatin and WAY-253623, 50 mg/kg). Changes in the HDL fraction were observed after 14d and were less pronounced than for LDL-c. Triglycerides and liver enzymes (ALT and AST) although transiently increased by WAY-252623 reverted to predose levels with time. Dose-dependent activation of ABCG1 gene expression on day 7 in whole blood was sustained throughout the study. Increases in ABCA1 mRNA were also observed on days 7 and 14 after which concentrations returned to baseline. Following Study II, liver tissues were harvested for evaluation of lipid accumulation. WAY-252623 increased hepatic cholesterol and TG content, as opposed to the phenotype observed in plasma following 28d of dosing. The possibility exists that hepatic accumulation may in fact reflect lipid transit through the liver resulting from increased reverse cholesterol transport rather than a direct effect of the compound on hepatic lipogenesis. Complementary microarray studies in liver and duodenum lend support to this interpretation. The data presented clearly indicate that WAY-252623 displays a unique and favorable profile in nonhuman primates, in distinct contrast to previously reported LXR agonists that increase plasma LDL cholesterol.