Click Chemistry on Solid Phase: Parallel Synthesis of N-Benzyltriazole Carboxamides as Super-Potent G-Protein Coupled Receptor Ligands

Abstract

The click chemistry-based backbone amide linker 1 was employed for an efficient and practical parallel synthesis of 1,2,3-triazole carboxamides when 1,3-dipolar cycloaddition was exploited for both the construction of a compound library and the functionalization of the resin. A three-step solid-phase-supported sequence included reductive amination by N-phenylpiperazinyl-substituted alkylamines, N-acylation by alkynoic acids, and azide-alkyne [3 + 2] cycloaddition. In most cases, cleavage under acidic conditions yielded the final products in excellent purities. A focused library of 60 target compounds was screened for G-protein coupled receptor binding employing eight biogenic amine receptors. Radioligand displacement experiments indicated a number of hit compounds revealing excellent receptor recognition when the methyl-substituted N-benzyltriazoles 29, 40, and 42 exhibited superior affinities for the alpha1 subtype (K(i) = 0.056-0.058 nM).