title: Novel acyl-CoA: cholesterol acyltransferase inhibitor: indoline-based sulfamide derivatives with low lipophilicity and protein binding ratio.
abstract: To find a novel acyl-CoA: cholesterol acyltransferase inhibitor, a series of sulfamide derivatives were synthesized and evaluated. Compound 1d, in which carboxymethyl moiety at the 5-position of Pactimibe was replaced by a sulfamoylamino group, showed 150-fold more potent anti-foam cell formation activity (IC(50): 0.02 microM), 1.6-fold higher log D(7.0) (4.63), and a slightly lower protein binding ratio (93.2%) than Pactimibe. Compound 1i, in which the octyl chain at the 1-position in 1d was replaced by an ethoxyethyl, showed markedly low log D(7.0) (1.73) and maintained 3-fold higher anti-foam cell formation activity (IC(50): 1.0 microM), than Pactimibe. The plasma protein binding ratio (PBR) of 1i was much lower than that of Pactimibe (62.5% vs. 98.1%), and its partition ratio to the rabbit atherosclerotic aorta after oral administration was higher than that of Pactimibe. Compound 1i at 10 microM markedly inhibited cholesterol esterification in atherosclerotic rabbit aortas even when incubated with serum, while Pactimibe had little effect probably due to its high PBR. In conclusion, compound 1i is expected to more efficiently inhibit the progression of atherosclerosis than Pactimibe.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., 38 Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masaru
authors.initials: M
authors.lastname: Ohta
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Shoji
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kasai
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kunishiro
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miike
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kanda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shirahase
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004951:Esterification; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D011485:Protein Binding; D011817:Rabbits; D012995:Solubility; D013237:Stereoisomerism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D013449:Sulfonamides; D002784:Cholesterol; D002785:Sterol O-Acyltransferase