title: Discovery of a novel acyl-CoA: cholesterol acyltransferase inhibitor: the synthesis, biological evaluation, and reduced adrenal toxicity of (4-phenylcoumarin)acetanilide derivatives with a carboxylic acid moiety.
abstract: As a part of our research for novel potent and orally available acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors that can be used as anti-atherosclerotic agents, we recently reported the discovery of the (4-phenylcoumarine)acetanilide derivative 1. However, compound 1 showed adrenal toxicity in animal models. In order to search for safer ACAT inhibitors that do not have adrenal toxicity, we examined the inhibitory activity of ACAT in human macrophage and adrenal cells. The introduction of a carboxylic acid moiety on the pendant phenyl ring and the adjustment of the lipophilicity led to the discovery of (2E)-3-[7-chloro-3-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]acrylic acid (21e), which showed potent ACAT inhibitory activity in macrophages and a selectivity of around 30-fold over adrenal cells. In addition, compound 21e showed high adrenal safety in guinea pigs.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa, Kanagawa 251–8555, Japan. Ogino_Masaki@takeda.co.jp
authors: Masaki
authors: M
authors: Ogino
authors: Yoshihisa
authors: Y
authors: Nakada
authors: Nobuyuki
authors: N
authors: Negoro
authors: Shigekazu
authors: S
authors: Itokawa
authors: Satoshi
authors: S
authors: Nishimura
authors: Tsukasa
authors: T
authors: Sanada
authors: Tomoko
authors: T
authors: Satomi
authors: Shunbun
authors: S
authors: Kita
authors: Kazuki
authors: K
authors: Kubo
authors: Shogo
authors: S
authors: Marui
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000214:Acyl Coenzyme A / Q000378:metabolism; D000284:Administration, Oral; D000302:Adrenal Cortex / Q000187:drug effects*; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D002264:Carboxylic Acids / Q000737:chemistry*; D002460:Cell Line; D003374:Coumarins / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D006168:Guinea Pigs; D006801:Humans; D023421:Models, Animal; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000083:Acetanilides; D000214:Acyl Coenzyme A; D000924:Anticholesteremic Agents; D002264:Carboxylic Acids; D003374:Coumarins; D004791:Enzyme Inhibitors; C094411:4-phenylcoumarin; D002785:Sterol O-Acyltransferase; C508827:acetanilide