title: Novel indoline-based acyl-CoA:cholesterol acyltransferase inhibitor with antiperoxidative activity: improvement of physicochemical properties and biological activities by introduction of carboxylic acid.
abstract: A series of novel indoline derivatives with an ionizable moiety were synthesized to find a bioavailable acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor with antiperoxidative activity. [7-(2,2-Dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic acid hemisulfate (2, pactimibe sulfate) with low lipophilicity and high water solubility showed good oral absorption and inhibitory activity against foam cell formation in THP-1 cells exposed to acetyl-LDL after differentiation (IC50: 0.3 microM) and an antiperoxidative effect in LDL of hypercholesterolemic rabbits (IC50: 1.0 microM). 2 inhibited macrophage, hepatic, and intestinal ACAT activity (IC50: 1.9, 0.7, and 0.7 microM, respectively). Maximal plasma concentration after oral administration of 2 at 10 mg/kg was 0.9 microg/mL in rats, 3.0 microg/mL in rabbits, and 11.2 microg/mL in dogs. Repeated administration of 2 lowered plasma LDL/VLDL cholesterol in hypercholesterolemic rabbits at 1 mg/kg/day, rats and dogs at 3 mg/kg/day, and in normocholesterolemic hamsters at 3 mg/kg/day. 2 is a promising candidate for antihyperlipidemic and antiatherosclerotic drugs.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kasai
authors.forename: Masaru
authors.initials: M
authors.lastname: Ohta
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Shoji
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kunishiro
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kanda
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kurahashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shirahase
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry*; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007211:Indoles; C057812:indoline; D002784:Cholesterol; D002785:Sterol O-Acyltransferase