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RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo.
- Source :
-
Journal of the American College of Cardiology [J Am Coll Cardiol] 2010 Jun 08; Vol. 55 (23), pp. 2580-9. - Publication Year :
- 2010
-
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.<br />Background: Increased apoA-I and HDL-C levels are potential therapeutic targets for reducing atherosclerotic disease.<br />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.<br />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.<br />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.<br /> (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- 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 Assessment
Apolipoprotein A-I blood
Apolipoprotein A-I drug effects
Cholesterol, HDL blood
Cholesterol, HDL drug effects
Quinazolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-3597
- Volume :
- 55
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of the American College of Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 20513599
- Full Text :
- https://doi.org/10.1016/j.jacc.2010.02.035