4-phenylcoumarin has been researched along with acetanilide* in 2 studies
2 other study(ies) available for 4-phenylcoumarin and acetanilide
| Article | Year |
|---|---|
Discovery of a potent and orally available acyl-CoA: cholesterol acyltransferase inhibitor as an anti-atherosclerotic agent: (4-phenylcoumarin)acetanilide derivatives.
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.). Topics: Acetamides; Acetanilides; Acyl Coenzyme A; Administration, Oral; Animals; Anticholesteremic Agents; Apolipoproteins; Atherosclerosis; Benzopyrans; Cholesterol; Coumarins; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Targeted Therapy; Structure-Activity Relationship | 2011 |
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.
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. Topics: Acetanilides; Acyl Coenzyme A; Administration, Oral; Adrenal Cortex; Animals; Anticholesteremic Agents; Carboxylic Acids; Cell Line; Coumarins; Enzyme Inhibitors; Guinea Pigs; Humans; Models, Animal; Rabbits; Sterol O-Acyltransferase | 2011 |