title: Novel indoline-based acyl-CoA: cholesterol acyltransferase inhibitor: Effects of introducing a methanesulfonamide group on physicochemical properties and biological activities.
abstract: A novel series of indoline-based acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors with a methanesulfonamide group at the 5-position were synthesized and their lipophilicity and biological activities were evaluated. Hepatic ACAT inhibitory and anti-foam cell formation activity increased dependent on lipophilicity of derivatives with various alkyl chains at the 1-position. The logD(7.0)-biological activity curve of the derivatives with a methanesulfonamide group shifted leftward compared to that of Pactimibe derivatives with a carboxymethyl group, and derivatives with no substituent, suggesting that a methanesulfonamide group plays an important role in the interaction with ACAT protein. Among derivatives, N-(1-ethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1b) had about twofold lower logD(7.0) than Pactimibe, while it showed twofold higher hepatic ACAT inhibition than and the same anti-foam cell formation as Pactimibe, respectively. The C(max) of 1b (10mg/kg, po) was higher than that of Pactimibe in rats. The plasma protein binding ratio of 1b was lower than that of Pactimibe: 64.8% and 97.9%, respectively. Compound 1b showed greater inhibitory effects on hepatic cholesterol secretion in mice than Pactimibe. In conclusion, the introduction of a methanesulfonamide group is effective to design less lipophilic, more efficacious and more bioavailable indoline-based ACAT inhibitors than previous indoline-based inhibitors.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Nishinokyo Tsukinowa-cho, Nakagyo-ku, Japan.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Shoji
authors.forename: Kenji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masaru
authors.initials: M
authors.lastname: Ohta
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kasai
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kunishiro
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kanda
authors.forename: Satoko
authors.initials: S
authors.lastname: Yogai
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shirahase
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D007210:Indoleacetic Acids; D007211:Indoles; C544484:N-(1-ethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide; D013449:Sulfonamides; C036871:methanesulfonamide; C057812:indoline; C509302:pactimibe; D002785:Sterol O-Acyltransferase