114958-19-9Relevant academic research and scientific papers
Inhibitors of acyl-CoA:cholesterol O-acetyltransferase (ACAT). Part 1: Identification and structure-activity relationships of a novel series of substituted N-alkyl-N-biphenylmethyl-N'-arylureas
Tanaka, Akira,Terasawa, Takeshi,Hagihara, Hiroyuki,Sakuma, Yuri,Ishibe, Noriko,Sawada, Masae,Takasugi, Hisashi,Tanaka, Hirokazu
, p. 15 - 30 (2007/10/03)
A series of N-alkyl-N-biphenylylmethyl-N'-arylurea and related derivatives represented by 1 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Linking of two phenyl groups via oxygen and introduction of fluorine at appropriate positions on the biphenyl moiety improved in vitro and in vivo activity. From this series of analogs, compound 40 (FR179254), which had potent in vitro potency (rabbit intestinal microsomes IC50 = 25 nM), showed excellent plasma cholesterol-lowering activity when administered via the diet (ED50 = 0.045 mg/kg). However, the hypocholesterolemic effect of this compound was moderate when dosed by oral gavage in PEG400 as a vehicle (ED50 = 5.3 mg/kg). Modification of the N'-aryl moiety led to the identification of compound 50 (FR182980) which was efficacious in both dosing models (ED50 = 0.034 mg/kg and 0.11 mg/kg, respectively).
Synthesis and Evaluation of Multisubstrate Inhibitors of an Oncogene-Encoded Tyrosine-Specific Protein Kinase. 1
Kruse, Carolyn H.,Holden, Kenneth G.,Pritchard, M. Lynn,Feild, John A.,Rieman, David J.,et al.
, p. 1762 - 1767 (2007/10/02)
The synthesis and testing of potental multisubstrate inhibitors of tyrosine-specific protein kinases are described.One of the substrates, ATP, was mimicked by the known kinase inhibitor 5'-adenosine, which was covalently linked via the sulfonyl moiety to tyrosine mimics.The resulting multisubstrate inhibitors were tested for their ability to inhibit the transfer of phosphate from ATP to a protein acceptor by p60v-abl, the tyrosine kinase encoded by the transforming gene (v-abl) of the Abelson murine leukemia virus (A-MuLV).Although the series of inhibitors displayed moderately potent activity (IC50 values as low as 19 μM), the absence of large effects produced by modification of the tyrosine mimic suggests that they do not behave as multisubstrate inhibitors but bind primarily through the adenosine moiety common to all the inhibitors.This interpretation is strengthened by the findings that the inhibitors lack specificity, inhibiting a serine kinase at compatible concentrations.
