A novel compound, R-138329, increases plasma HDL cholesterol via inhibition of scavenger receptor BI-mediated selective lipid uptake.
High-density lipoprotein (HDL) has a protective effect against atherosclerosis. Therefore, a compound that elevates the plasma HDL cholesterol (HDL-C) levels is expected to be a promising anti-atherosclerotic agent. We discovered a novel compound, R-138329, that increased HDL-C by 41% in normolipidemic hamsters at a dose of 100mg/kg. To investigate the mechanism of action of R-138329, we examined the effect of R-138329 on the clearance of [(3)H]cholesterol ether ([(3)H]COE)-labeled and [(125)I]-labeled HDL in mice. R-138329 delayed the clearance of [(3)H]COE-labeled HDL and reduced accumulation of tracer HDL in the liver, whereas the clearance of [(125)I]-labeled HDL particles was unaffected by the compound. In vitro analysis showed that R-154716, a metabolite of R-138329, dramatically inhibited the uptake of [(3)H]COE-labeled HDL in McA-RH 7777 rat hepatoma cells. Furthermore, 100 nM of R-154716 completely inhibited [(3)H]COE-labeled HDL uptake induced by overexpression of scavenger receptor BI (SR-BI) in HEK293 cells. Taken together, these findings suggest that the mechanism by which R-138329 elevates HDL-C in vivo is principally involved in the inhibition of SR-BI-mediated selective lipid uptake in the liver.
Nishizawa
Tomohiro
T
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. nisizawa@sankyo.co.jp
Kitayama
Ken
K
Wakabayashi
Kenji
K
Yamada
Makiko
M
Uchiyama
Minoru
M
Abe
Koji
K
Ubukata
Naoko
N
Inaba
Toshimori
T
Oda
Tomiichiro
T
Amemiya
Yoshiya
Y
D000818:Animals; D018955:CD36 Antigens / Q000187:drug effects*; D002461:Cell Line, Transformed; D008076:Cholesterol, HDL / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008647:Mesocricetus; D051379:Mice; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics
D018955:CD36 Antigens; D008076:Cholesterol, HDL; C521768:N-(4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl)-(2-chloro-5-nitrophenyl)carboxamide; D010879:Piperazines; C521770:R-154716; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B