Anti-hyperlipidemic action of a newly synthesized benzoic acid derivative, S-2E.
A newly synthesized benzoic acid derivative, (+)-(S)-p-[1-(p-tert-butylphenyl)-2-oxo-4-pyrrolidinyl]methoxybenzoic acid (S-2E), has the capacity to inhibit the biosynthesis of both sterol and fatty acids. Here, we report the mechanism by which S-2E lowers blood cholesterol and triglyceride levels. In the liver, S-2E was converted into its active metabolite, S-2E-CoA. S-2E-CoA noncompetitively inhibited the enzymatic activities of both 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and acetyl-CoA carboxylase at K(i)=18.11 microM and K(i)=69.2 microM, respectively. Interestingly, pharmacokinetic experiments in rats showed that the concentration of S-2E-CoA in the liver was sufficient to inhibit the activities of HMG-CoA reductase and acetyl-CoA carboxylase, for example, when orally given to rats at 10 mg/kg. Indeed, S-2E (3-30 mg/kg) given orally suppressed the secretion rate of very-low-density lipoprotein (VLDL)-cholesterol and triglyceride in Triton WR-1339-injected rats. Furthermore, S-2E lowered the blood total cholesterol and triglyceride levels simultaneously in Zucker fatty rats. Collectively, S-2E may be useful in the treatment of familial hypercholesterolemia and mixed hyperlipidemia.
Ohmori
Koichi
K
Pharmacobioregulation Research Laboratory, Taiho Pharmaceutical Co., Ltd., 1-27 Misugidai, Saitama 357-8527, Hanno, Japan.
Yamada
Haruo
H
Yasuda
Akio
A
Yamamoto
Akira
A
Matsuura
Naosuke
N
Kiniwa
Mamoru
M
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D005227:Fatty Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D062425:Hydroxybenzoate Ethers; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008079:Lipoproteins, VLDL / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker / Q000235:genetics / Q000378:metabolism; D013261:Sterols / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013535:Suspensions; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
C482648:4-(1-(4-tert-butylphenyl)-2-oxo-4-pyrrolidinyl)methoxybenzoic acid; D000214:Acyl Coenzyme A; D001565:Benzoates; D005227:Fatty Acids; D062425:Hydroxybenzoate Ethers; D000960:Hypolipidemic Agents; D008079:Lipoproteins, VLDL; D011760:Pyrrolidinones; D013261:Sterols; D013535:Suspensions; D014280:Triglycerides; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D002784:Cholesterol; D000103:Acetyl-CoA Carboxylase