title: 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).
authors.affiliation: Department of Medicinal Chemistry, Emil Fisher Center, Friedrich Alexander University, Schuhstrasse 19, D-91052, Erlangen, Germany.
authors.forename: Pilar Rodriguez
authors.initials: PR
authors.lastname: Loaiza
authors.forename: Stefan
authors.initials: S
authors.lastname: Löber
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D002264:Carboxylic Acids; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014230:Triazoles / Q000138:chemical synthesis*
chemical_list: D002264:Carboxylic Acids; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles