Discovery and development of dimeric podocarpic acid leads as potent agonists of liver X receptor with HDL cholesterol raising activity in mice and hamsters.
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.
Singh
Sheo B
SB
Merck Research Laboratories, Rahway, NJ 07065, USA. sheo_singh@merck.com
Ondeyka
John G
JG
Liu
Weiguo
W
Chen
Steve
S
Chen
Tom S
TS
Li
Xiaohua
X
Bouffard
Aileen
A
Dropinski
James
J
Jones
A Brian
AB
McCormick
Sherrie
S
Hayes
Nancy
N
Wang
Jianhua
J
Sharma
Neelam
N
Macnaul
Karen
K
Hernandez
Melba
M
Chao
Yu-Sheng
YS
Baffic
Joanne
J
Lam
My-Hanh
MH
Burton
Charlotte
C
Sparrow
Carl P
CP
Menke
John G
JG
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
D045784:Abietanes; D008076:Cholesterol, HDL; D010616:Phenanthrenes; D018160:Receptors, Cytoplasmic and Nuclear; C002470:podocarpic acid