1. Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis.
- Author
-
Hu B, Collini M, Unwalla R, Miller C, Singhaus R, Quinet E, Savio D, Halpern A, Basso M, Keith J, Clerin V, Chen L, Resmini C, Liu QY, Feingold I, Huselton C, Azam F, Farnegardh M, Enroth C, Bonn T, Goos-Nilsson A, Wilhelmsson A, Nambi P, and Wrobel J
- Subjects
- ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters biosynthesis, Animals, Anticholesteremic Agents chemistry, Anticholesteremic Agents pharmacology, Binding Sites, Biological Availability, Cell Line, Cholesterol metabolism, DNA-Binding Proteins genetics, Drug Stability, Female, Humans, In Vitro Techniques, Ligands, Liver X Receptors, Male, Mice, Mice, Inbred C57BL, Microsomes, Liver metabolism, Models, Molecular, Molecular Structure, Orphan Nuclear Receptors, Phenylacetates chemistry, Phenylacetates pharmacology, Protein Structure, Tertiary, Quinolines chemistry, Quinolines pharmacology, Receptors, Cytoplasmic and Nuclear genetics, Structure-Activity Relationship, Transcriptional Activation, Anticholesteremic Agents chemical synthesis, Atherosclerosis drug therapy, DNA-Binding Proteins agonists, Phenylacetates chemical synthesis, Quinolines chemical synthesis, Receptors, Cytoplasmic and Nuclear agonists
- Abstract
A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
- Published
- 2006
- Full Text
- View/download PDF