Design, synthesis, and structure-activity relationship of podocarpic acid amides as liver X receptor agonists for potential treatment of atherosclerosis.
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.
Liu
Weiguo
W
Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. weiguo_liu@merck.com
Chen
Steve
S
Dropinski
James
J
Colwell
Lawrence
L
Robins
Michael
M
Szymonifka
Michael
M
Hayes
Nancy
N
Sharma
Neelam
N
MacNaul
Karen
K
Hernandez
Melba
M
Burton
Charlotte
C
Sparrow
Carl P
CP
Menke
John G
JG
Singh
Sheo B
SB
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
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