Influence of various central moieties on the hypolipidemic properties of long hydrocarbon chain diols and diacids.
A series of long (11-15) hydrocarbon chain diols and diacids with various central functional groups and terminal gem-dimethyl or -methyl/aryl substituents was synthesized and evaluated in both in vivo and in vitro assays for its potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes, as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats, Crl:(ZUC)-faBR. The most active compounds were hydroxyl-substituted symmetrical diacids and diols with a 13-atom chain and terminal gem-dimethyl substituents. Furthermore, biological activity was enhanced by central substitution with O, C=O, S, S=O compared to the methylene analogues and was diminished for compounds with central functional groups such as carbamate, ester, urea, acetylmethylene, and hydroxymethylene.
Oniciu
Daniela C
DC
Esperion Therapeutics, A Division of Pfizer Global Research and Development, 3621 South State Street, 695 KMS Place, Ann Arbor, Michigan 48108, USA. oniciu@yahoo.com
Dasseux
Jean-Louis H
JL
Yang
Jing
J
Mueller
Ralf
R
Pop
Emil
E
Denysenko
Anna
A
Duan
Caiming
C
Huang
Tian-Bao
TB
Zhang
Lianhao
L
Krause
Brian R
BR
Drake
Sandra L
SL
Lalwani
Narendra
N
Cramer
Clay T
CT
Goetz
Brian
B
Pape
Michael E
ME
McKee
Andrew
A
Fici
Gregory J
GJ
Lutostanski
Janell M
JM
Brown
Stephen C
SC
Bisgaier
Charles L
CL
D000284:Administration, Oral; D000438:Alcohols / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D022781:Hepatocytes / Q000187:drug effects; D006838:Hydrocarbons / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008055:Lipids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015394:Molecular Structure; D051381:Rats; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D013997:Time Factors
D000438:Alcohols; D003998:Dicarboxylic Acids; D006838:Hydrocarbons; D000960:Hypolipidemic Agents; D008055:Lipids