Synthesis and structure–activity relationships of N-(4-amino-2,6-diisopropylphenyl)-N’-(1,4-diarylpiperidine-4-yl)methylureas as anti-hyperlipidemic agents

A Novel Class of Antihyperlipidemic Agents with Low Density Lipoprotein Receptor Up-Regulation via the Adaptor Protein Autosomal Recessive Hypercholesterolemia

“…Compound 45 with a phenolic hydroxyl group showed no activity, and replacement of the methoxy group with an ethoxy or propoxy group ( 46 or 47 ), or a hydroxyalkoxy group ( 48 or 49 ) was also unfavorable, giving decreased activity due to elongation of the alkyl chain. These findings suggested that a methoxy group could be the most suitable substituent at this position, a result which does not agree with our previous work …”

“…On the basis of these findings, we could confirm that the mechanism of LDL-R up-regulation is independent of ACAT inhibition. As we have previously disclosed the structure−activity relationship (SAR) of A-part (Figure ) and shown that introduction of 2-methoxyphenyl group in this part provides favorable results, our work in this study was mainly focused on using an alkoxyphenyl or an alkoxypyridyl as substituent. An aromatic group in the A-part is essential for ACAT inhibition.…”

“…The compounds synthesized in this study and their synthetic methods are shown in Schemes −. The nitriles 3 and 4 were hydrolyzed with aqueous 6N KOH solution at 130 °C in DMSO to give the carboxamides 5 and 6 , respectively. The carboxamides, thus obtained, were converted to the corresponding carboxylic acids ( 7 and 8 ) by acidic hydrolysis with concentrated hydrochloric acid solution at 90 °C.…”

“…We have previously reported a novel antihyperlipidemic agent 1 (SMP-797) and described 1,4-diarylpiperidine-4-methylurea derivative 2 as its back-up compounds (Figure ). Compounds 1 and 2 possess dual activity consisting of inhibition of cholesterol O -acyltransferase (ACAT) and up-regulation of LDL-R.…”

Selective alkylation of aminophenols

“…They have been widely used in the synthesis of pharmaceutical agents, [1][2][3][4] such as non-peptide full agonists for the human bradykinin B 2 receptor 1 and cholesterol acyltransferase inhibitors, 2 and chiral ligands for asymmetric catalysis. 5,6 Both of alkoxyanilines and N-alkylaminophenols can be prepared from aminophenols via alkylation.…”