title: Long hydrocarbon chain keto diols and diacids that favorably alter lipid disorders in vivo.
abstract: Keto-substituted hydrocarbons with 11-19 methylene and bis-terminal hydroxyl and carboxyl groups have been synthesized and evaluated in both in vivo and in vitro assays for their 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] following 1 and 2 weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ketone functionality and the gem dimethyl or methyl/aryl substituents. Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g, 14c), and the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f, 14f). Compound 14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with a minimum effective dose of 30 mg/kg/day. Compound 1 g dose-dependently modified non-HDL-cholesterol, triglycerides, and nonesterified fatty acids, with a minimum effective dose of 10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2-3 times higher than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels was observed.
authors.affiliation: Alchem Laboratories Corporation, 13305 Rachael Boulevard, Alachua, Florida 32615, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Mueller
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Caiming
authors.initials: C
authors.lastname: Duan
authors.forename: Emil
authors.initials: E
authors.lastname: Pop
authors.forename: Otto J
authors.initials: OJ
authors.lastname: Geoffroy
authors.forename: Lian Hao
authors.initials: LH
authors.lastname: Zhang
authors.forename: Tian-Bao
authors.initials: TB
authors.lastname: Huang
authors.forename: Sergey
authors.initials: S
authors.lastname: Denisenko
authors.forename: Bruce H
authors.initials: BH
authors.lastname: McCosar
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Oniciu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bisgaier
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pape
authors.forename: Catherine Delaney
authors.initials: CD
authors.lastname: Freiman
authors.forename: Brian
authors.initials: B
authors.lastname: Goetz
authors.forename: Clay T
authors.initials: CT
authors.lastname: Cramer
authors.forename: Krista L
authors.initials: KL
authors.lastname: Hopson
authors.forename: Jean-Louis H
authors.initials: JL
authors.lastname: Dasseux
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000096:biosynthesis / Q000097:blood; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006838:Hydrocarbons / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006949:Hyperlipidemias / Q000188:drug therapy / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007651:Keto Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: C494560:2,2,14,14-tetramethyl-8-oxopentadecanedioic acid; D000438:Alcohols; D008076:Cholesterol, HDL; D003998:Dicarboxylic Acids; D006838:Hydrocarbons; D000960:Hypolipidemic Agents; D007651:Keto Acids; D007659:Ketones; D008055:Lipids