ABSTRACT
OBJECTIVES: The aim of this study was to determine whether a novel small molecule RVX-208 affects apolipoprotein (apo)A-I and high-density lipoprotein cholesterol (HDL-C) levels in vitro and in vivo. BACKGROUND: Increased apoA-I and HDL-C levels are potential therapeutic targets for reducing atherosclerotic disease. METHODS: HepG2 cells were treated with 0 to 60 mumol/l RVX-208 followed by assays for apoA-I and HDL-C production. For in vivo studies, African green monkeys (AGMs) received 15 to 60 mg/kg/day RVX-208, and the serum was analyzed for lipoprotein levels, HDL-subparticle distribution, cholesterol efflux, and activity of lipid-modifying enzymes. A phase I clinical trial was conducted in healthy volunteers (given 1 to 20 mg/kg/day of RVX-208) to assess safety, tolerability, and pharmacokinetics. RESULTS: The RVX-208 induced apoA-I messenger ribonucleic acid and protein synthesis in HepG2 cells, leading to increased levels of pre-beta-migrating and alpha-lipoprotein particles containing apoA-I (LpA-I) in spent media. Similarly, in AGMs, RVX-208 treatment for 63 days increased serum apoA-I and HDL-C levels (60% and 97%, respectively). In addition, the levels of pre-beta(1)-LpA-I and alpha1-LpA-I HDL-subparticles were increased as well as adenosine triphosphate binding cassette AI, adenosine triphosphate binding cassette G1, and scavenger receptor class B type I-dependent cholesterol efflux. These changes were not mediated by cholesteryl-ester-transfer protein. Treatment of humans for 1 week with oral RVX-208 increased apoA-I, pre-beta-HDL, and HDL functionality. CONCLUSIONS: RVX-208 increases apoA-I and HDL-C in vitro and in vivo. In AGMs, RVX-208 raises serum pre-beta(1)-LpA-I and alpha-LpA-I levels and enhances cholesterol efflux. Data in humans point to beneficial features of RVX-208 that might be useful for treating atherosclerosis.
Subject(s)
Apolipoprotein A-I/blood , Apolipoprotein A-I/drug effects , Cholesterol, HDL/blood , Cholesterol, HDL/drug effects , Quinazolines/pharmacology , Animals , Apolipoprotein A-I/biosynthesis , Apolipoprotein A-I/metabolism , Cells, Cultured , Chlorocebus aethiops , Cholesterol, HDL/metabolism , Cricetinae , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Hep G2 Cells/drug effects , Hep G2 Cells/metabolism , Humans , In Vitro Techniques , Macaca fascicularis , Male , Molecular Weight , Probability , Quinazolines/chemistry , Quinazolinones , Random Allocation , Risk AssessmentABSTRACT
Based on the naturally occurring stilbene, Resveratrol, a series of novel stilbene derivatives were synthesized, which have the ability to induce the expression of the ApoA-I gene. Several compounds equally or more potent than Resveratrol were identified. trans-4,4'-dihydroxy-2-methoxystilbene was the most potent (4.6x more potent than Resveratrol). These compounds provide an early lead into new drugs to treat atherosclerosis.
