title: Design, synthesis, and structure-activity relationship of podocarpic acid amides as liver X receptor agonists for potential treatment of atherosclerosis.
abstract: A series of podocarpic acid amides were identified as potent agonists for Liver X receptor alpha and beta subtypes, which are members of a nuclear hormone receptor superfamily that are involved in the regulation of a variety of metabolic pathways including cholesterol metabolism. We recently reported podocarpic acid anhydride and imide dimers as potent LXR agonists. Through parallel organic synthesis, we rapidly identified a series of new podocarpate leads with stable structures exemplified by adamantyl- and phenylcyclohexylmethyl-podocarpic acid amides (14 and 18). Compound 18 exhibited LXRalpha/beta 50/20 nM (binding affinity) and 33.7/35.3-fold receptor inductions. Synthesis, SAR, and biological activities of new podocarpate analogs are discussed.
authors.affiliation: Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. weiguo_liu@merck.com
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.forename: Steve
authors.initials: S
authors.lastname: Chen
authors.forename: James
authors.initials: J
authors.lastname: Dropinski
authors.forename: Lawrence
authors.initials: L
authors.lastname: Colwell
authors.forename: Michael
authors.initials: M
authors.lastname: Robins
authors.forename: Michael
authors.initials: M
authors.lastname: Szymonifka
authors.forename: Nancy
authors.initials: N
authors.lastname: Hayes
authors.forename: Neelam
authors.initials: N
authors.lastname: Sharma
authors.forename: Karen
authors.initials: K
authors.lastname: MacNaul
authors.forename: Melba
authors.initials: M
authors.lastname: Hernandez
authors.forename: Charlotte
authors.initials: C
authors.lastname: Burton
authors.forename: Carl P
authors.initials: CP
authors.lastname: Sparrow
authors.forename: John G
authors.initials: JG
authors.lastname: Menke
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D045784:Abietanes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use*; D000577:Amides / Q000737:chemistry*; D000818:Animals; D019540:Area Under Curve; D050197:Atherosclerosis / Q000188:drug therapy*; D002853:Chromatography, Liquid; D004268:DNA-Binding Proteins / Q000819:agonists*; D000071518:Liver X Receptors; D008297:Male; D013058:Mass Spectrometry; D057093:Orphan Nuclear Receptors; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D045784:Abietanes; D000577:Amides; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D010616:Phenanthrenes; D018160:Receptors, Cytoplasmic and Nuclear; C002470:podocarpic acid