title: Influence of various central moieties on the hypolipidemic properties of long hydrocarbon chain diols and diacids.
abstract: 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.
authors.affiliation: 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
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Oniciu
authors.forename: Jean-Louis H
authors.initials: JL
authors.lastname: Dasseux
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Ralf
authors.initials: R
authors.lastname: Mueller
authors.forename: Emil
authors.initials: E
authors.lastname: Pop
authors.forename: Anna
authors.initials: A
authors.lastname: Denysenko
authors.forename: Caiming
authors.initials: C
authors.lastname: Duan
authors.forename: Tian-Bao
authors.initials: TB
authors.lastname: Huang
authors.forename: Lianhao
authors.initials: L
authors.lastname: Zhang
authors.forename: Brian R
authors.initials: BR
authors.lastname: Krause
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Drake
authors.forename: Narendra
authors.initials: N
authors.lastname: Lalwani
authors.forename: Clay T
authors.initials: CT
authors.lastname: Cramer
authors.forename: Brian
authors.initials: B
authors.lastname: Goetz
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pape
authors.forename: Andrew
authors.initials: A
authors.lastname: McKee
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Fici
authors.forename: Janell M
authors.initials: JM
authors.lastname: Lutostanski
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Brown
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bisgaier
mesh_terms: 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
chemical_list: D000438:Alcohols; D003998:Dicarboxylic Acids; D006838:Hydrocarbons; D000960:Hypolipidemic Agents; D008055:Lipids