LXR-623

LXR-623 is an agonist of liver X-receptor with IC50 values of 179nM and 24nM for LXR-α and LXR-β, respectively [1].

LXR-623 is a partial agonist of LXR which regulates the transcription of genes involved in cellular cholesterol homeostasis. As the LXR agonist, LXR-623 is used to enhance reverse cholesterol transport through up-regulating cholesterol transporters. To rodents, orally dosed LXR-623 increases the transcription level of ABCA1 and ABCG1 in peripheral blood cells. To human, LXR-623 also significantly increases ABCA1 and ABCG1 both in PBMC cells and in T- and B-cells. In addition, in mouse model of atherosclerosis, LXR-623 is found to up-regulate intestinal ABCG5 and ABCG8. In cynomolgus monkeys, LXR-623 up-regulates ABCA1 and ABCG1 in whole blood. Besides that, LXR-623 is proposed to be used in treatment of Alzheimer’s disease since it can lower the level of amyloid-βin brain [1, 2].

References:
[1] Katz A, Udata C, Ott E, et al. Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of LXR‐623, a Novel Liver X‐Receptor Agonist, in Healthy Participants. The Journal of Clinical Pharmacology, 2009, 49(6): 643-649.
[2] DiBlasio-Smith E A, Arai M, Quinet E M, et al. Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells. J Transl Med, 2008, 6: 59.

Safety, pharmacokinetics, and pharmacodynamics of single doses of LXR-623, a novel liver X-receptor agonist, in healthy participants.[Pubmed:19398602]

J Clin Pharmacol. 2009 Jun;49(6):643-9.

Liver X-receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate-binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR-623 is a synthetic ligand for LXRs alpha and beta that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy participants. LXR-623 was absorbed rapidly with peak concentrations (C(max)) achieved at approximately 2 hours. The C(max) and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose-dependent increase in ABCA1 and ABCG1 expression. The effect of LXR-623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic-pharmacodynamic analysis, yielding EC(50) estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system-related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of "target engagement" by an LXR agonist in humans.

LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse.[Pubmed:19318684]

J Lipid Res. 2009 Dec;50(12):2358-70.

Liver X receptors (LXRs) are ligand-activated transcription factors that coordinate regulation of gene expression involved in several cellular functions but most notably cholesterol homeostasis encompassing cholesterol transport, catabolism, and absorption. WAY-252623 (LXR-623) is a highly selective and orally bioavailable synthetic modulator of LXR, which demonstrated efficacy for reducing lesion progression in the murine LDLR(-/-) atherosclerosis model with no associated increase in hepatic lipogenesis either in this model or Syrian hamsters. In nonhuman primates with normal lipid levels, WAY-252623 significantly reduced total (50-55%) and LDL-cholesterol (LDLc) (70-77%) in a time- and dose-dependent manner as well as increased expression of the target genes ABCA1/G1 in peripheral blood cells. Statistically significant decreases in LDLc were noted as early as day 7, reached a maximum by day 28, and exceeded reductions observed for simvastatin alone (20 mg/kg). Transient increases in circulating triglycerides and liver enzymes reverted to baseline levels over the course of the study. Complementary microarray analysis of duodenum and liver gene expression revealed differential activation of LXR target genes and suggested no direct activation of hepatic lipogenesis. WAY-252623 displays a unique and favorable pharmacological profile suggesting synthetic LXR ligands with these characteristics may be suitable for evaluation in patients with atherosclerotic dyslipidemia.

Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells.[Pubmed:18925943]

J Transl Med. 2008 Oct 16;6:59.

BACKGROUND: LXRs (Liver X Receptor alpha and beta) are nuclear receptors that act as ligand-activated transcription factors. LXR activation causes upregulation of genes involved in reverse cholesterol transport (RCT), including ABCA1 and ABCG1 transporters, in macrophage and intestine. Anti-atherosclerotic effects of synthetic LXR agonists in murine models suggest clinical utility for such compounds. OBJECTIVE: Blood markers of LXR agonist exposure/activity were sought to support clinical development of novel synthetic LXR modulators. METHODS: Transcript levels of LXR target genes ABCA1 and ABCG1 were measured using quantitative reverse transcriptase/polymerase chain reaction assays (qRT-PCR) in peripheral blood from mice and rats (following a single oral dose) and monkeys (following 7 daily oral doses) of synthetic LXR agonists. LXRalpha, LXRbeta, ABCA1, and ABCG1 mRNA were measured by qRT-PCR in human peripheral blood mononuclear cells (PBMC), monocytes, T- and B-cells treated ex vivo with WAY-252623 (LXR-623), and protein levels in human PBMC were measured by Western blotting. ABCA1/G1 transcript levels in whole-blood RNA were measured using analytically validated assays in human subjects participating in a Phase 1 SAD (Single Ascending Dose) clinical study of LXR-623. RESULTS: A single oral dose of LXR agonists induced ABCA1 and ABCG1 transcription in rodent peripheral blood in a dose- and time-dependent manner. Induction of gene expression in rat peripheral blood correlated with spleen expression, suggesting LXR gene regulation in blood has the potential to function as a marker of tissue gene regulation. Transcriptional response to LXR agonist was confirmed in primates, where peripheral blood ABCA1 and ABCG1 levels increased in a dose-dependent manner following oral treatment with LXR-623. Human PBMC, monocytes, T- and B cells all expressed both LXRalpha and LXRbeta, and all cell types significantly increased ABCA1 and ABCG1 expression upon ex vivo LXR-623 treatment. Peripheral blood from a representative human subject receiving a single oral dose of LXR-623 showed significant time-dependent increases in ABCA1 and ABCG1 transcription. CONCLUSION: Peripheral blood cells express LXRalpha and LXRbeta, and respond to LXR agonist treatment by time- and dose-dependently inducing LXR target genes. Transcript levels of LXR target genes in peripheral blood are relevant and useful biological indicators for clinical development of synthetic LXR modulators.