Click chemistry on solid phase: parallel synthesis of N-benzyltriazole carboxamides as super-potent G-protein coupled receptor ligands

Journal of Combinatorial Chemistry
Pilar Rodriguez LoaizaPeter Gmeiner

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).

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Citations

Jul 10, 2010·Journal of Combinatorial Chemistry·Jitendra K MishraSubhash C Sinha
Dec 15, 2015·ACS Combinatorial Science·Vida CastroFernando Albericio
Jul 14, 2009·Bioorganic & Medicinal Chemistry·Pilar Rodriguez LoaizaPeter Gmeiner
Sep 11, 2007·Bioorganic & Medicinal Chemistry·Pilar Rodriguez LoaizaPeter Gmeiner
Jan 25, 2008·ChemMedChem·A D Moorhouse, J E Moses
Nov 18, 2006·Angewandte Chemie·Bruce H Lipshutz, Benjamin R Taft
Jun 27, 2017·Chemistry : a European Journal·Daniel LachmannBurkhard König
Mar 18, 2009·Chemical Reviews·Ulrik BoasKnud J Jensen
May 9, 2009·The Journal of Organic Chemistry·Katherine A DaviesJeremy E Wulff
Sep 20, 2007·Journal of Combinatorial Chemistry·Roland E DolleWei Zhang
Aug 14, 2008·Chemical Reviews·Morten Meldal, Christian Wenzel Tornøe
Nov 17, 2009·The Journal of Organic Chemistry·David P DicksonChad L Landrie
Jun 3, 2008·Journal of Combinatorial Chemistry·Sebastián A Testero, Ernesto G Mata
May 17, 2014·Journal of Medicinal Chemistry·Dorothee MöllerPeter Gmeiner
Mar 28, 2013·Chemical Reviews·Prakasam ThirumuruganKrzysztof Jozwiak

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