The medicinal chemistry of liver X receptor (LXR) modulators.
LXRs have been of interest as targets for the treatment of atherosclerosis for over a decade. In recent years, LXR modulators have also garnered interest for potential use in the treatment of inflammation, Alzheimer's disease (AD), dermatological conditions, hepatic steatosis, and oncology. To date, no LXR modulator has successfully progressed beyond phase I clinical trials. In this Perspective, we summarize published medicinal chemistry efforts in the context of the available crystallographic data, druglikeness, and isoform selectivity. In addition, we discuss the challenges that need to be overcome before an LXR modulator can reach clinical use.
Vitae Pharmaceuticals Inc. , 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
Colin M
CM
Tice
Paul B
PB
Noto
Kristi Yi
KY
Fan
Linghang
L
Zhuang
Deepak S
DS
Lala
Suresh B
SB
Singh
D000924:Anticholesteremic Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000071518:Liver X Receptors; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism; D020033:Protein Isoforms / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D001565:Benzoates; D001596:Benzylamines; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D013449:Sulfonamides; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides