title: Discovery and development of dimeric podocarpic acid leads as potent agonists of liver X receptor with HDL cholesterol raising activity in mice and hamsters.
abstract: Liver X receptors are nuclear receptors that regulate metabolism of cholesterol. They are activated by oxysterols resulting in increased transcription of the ABCA1 gene, promoting cholesterol efflux and HDL formation. We have identified podocarpic acid anhydride as a 1nM agonist of LXRalpha and beta receptors. Functionally this agonist was over 8-10-fold better activator of LXR receptors compared to one of the natural ligands, 22-(R)-hydroxy cholesterol, in HEK-293 cells. An imide analog increased the level of HDL by 26%, decreased LDL by 10.6%, and increased triglyceride by 51% in hamsters. Discovery, synthesis, SAR and details of the activities of dimers have been described.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA. sheo_singh@merck.com
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: John G
authors.initials: JG
authors.lastname: Ondeyka
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.forename: Steve
authors.initials: S
authors.lastname: Chen
authors.forename: Tom S
authors.initials: TS
authors.lastname: Chen
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Aileen
authors.initials: A
authors.lastname: Bouffard
authors.forename: James
authors.initials: J
authors.lastname: Dropinski
authors.forename: A Brian
authors.initials: AB
authors.lastname: Jones
authors.forename: Sherrie
authors.initials: S
authors.lastname: McCormick
authors.forename: Nancy
authors.initials: N
authors.lastname: Hayes
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
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: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Joanne
authors.initials: J
authors.lastname: Baffic
authors.forename: My-Hanh
authors.initials: MH
authors.lastname: Lam
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
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D002460:Cell Line; D008076:Cholesterol, HDL / Q000097:blood*; D006224:Cricetinae; D019281:Dimerization; D006801:Humans; D008297:Male; D051379:Mice; D010616:Phenanthrenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D045784:Abietanes; D008076:Cholesterol, HDL; D010616:Phenanthrenes; D018160:Receptors, Cytoplasmic and Nuclear; C002470:podocarpic acid