title: Discovery of a potent and orally available acyl-CoA: cholesterol acyltransferase inhibitor as an anti-atherosclerotic agent: (4-phenylcoumarin)acetanilide derivatives.
abstract: Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure-activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan. Ogino_Masaki@takeda.co.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Ogino
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukui
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakada
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tokunoh
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Itokawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kakoi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sanada
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Fuse
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kubo
authors.forename: Takeo
authors.initials: T
authors.lastname: Wada
authors.forename: Shogo
authors.initials: S
authors.lastname: Marui
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000083:Acetanilides / Q000737:chemistry; D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001053:Apolipoproteins / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism; D003374:Coumarins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D013329:Structure-Activity Relationship
chemical_list: C573105:2-(7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl)-N-(4-chloro-2-(trifluoromethyl)phenyl)acetamide; D000081:Acetamides; D000083:Acetanilides; D000214:Acyl Coenzyme A; D000924:Anticholesteremic Agents; D001053:Apolipoproteins; D001578:Benzopyrans; D003374:Coumarins; D004791:Enzyme Inhibitors; C094411:4-phenylcoumarin; D002784:Cholesterol; C508827:acetanilide