Synthesis of New Trisubstituted 4‐Aminopiperidines as PAF‐Receptor Antagonists

Abstract

Two novel classes of 4-aminopiperidines substituted in the 3-position by groups bearing either a carbamate or a ureido function have been synthesized from ethyl 4-oxo-3-piperidinecarboxylate and 3,3Ј-iminobis(propanenitrile), respectively. The key step in this synthesis, the reduction of the piperidinic β-enamino ester or nitrile, occurred readily. In contrast to published works, the free primary amines could be isolated from the corresponding β-amino ester or nitrile.

Progress in the Development of Platelet‐Activating Factor Receptor (PAFr) Antagonists and Applications in the Treatment of Inflammatory Diseases

“…SAR data revealed that the replacement of the piperazine core with the aminopiperidine motif did not change the ability of molecules to bind the PAFr. Although there were marked differences in PAFr binding activity associated with various diastereomers used in this study, a clear trend was not evident …”

“…In silico modeling studies have identified some key features of the PAFr binding site, but crystallographic data and protein structural modeling are required to accurately elucidate the binding properties of the PAFr . It has been proposed that the binding site of the PAFr consists of a bipolarized cylinder ≈10–12 Å in diameter, and a second, shorter domain ≈6–7 Å in diameter . Recent reports even suggest that the binding site may consist of a tetrapolarized cylinder .…”

“…It has been proposed that the binding site of the PAFr consists of a bipolarized cylinder ≈10–12 Å in diameter, and a second, shorter domain ≈6–7 Å in diameter . Recent reports even suggest that the binding site may consist of a tetrapolarized cylinder . Work has also been undertaken toward the design of a pseudo‐receptor .…”

“…Significant research over the past decade has generated SAR data for non‐diazepine‐based synthetic molecules and some natural products . In contrast, seminal SAR studies relating to diazepine‐type compounds were reported over 25 years ago, and there have been few major developments since this time .…”

“…A number of new trisubstituted 4‐aminopiperidines 18 were prepared as alternatives to previously reported piperazine antagonists (Figure ) . These heterocycles featured improved conformational flexibility and greater distances between the key N‐substituents.…”