title: Solution-phase parallel synthesis of ruxolitinib-derived Janus kinase inhibitors via copper-catalyzed azide-alkyne cycloaddition.
abstract: A solution-phase parallel synthesis of triazole-derived ruxolitinib analogues was developed in the current study. The method employs copper-catalyzed azide-alkyne cycloaddition to build up the central triazole template. Product isolation by precipitation and centrifugation is straightforward and yields high purity compounds suited for biological profiling. A simple protocol for accessing the terminal alkyne precursors in high yields was established and a library of ruxolitinib-like triazoles featuring diverse functional groups was prepared. In addition, a model for the binding mode of ruxolitinib to Janus kinase (JAK) 2 is proposed. In contrast to previous models, the pose explains the compound selectivity for JAK1/JAK2 and is in accordance with published structure-activity data. On this basis, a structure-based design hypothesis for inverting the selectivity profile of ruxolitinib is deduced. Application of this strategy identified a moderately potent JAK3 inhibitor (35 nM) with high selectivity against other JAKs, potentially exploiting a covalent binding mode.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tuebingen , Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gehringer
authors.forename: Michael
authors.initials: M
authors.lastname: Forster
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D001386:Azides / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D061565:Cycloaddition Reaction; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D009570:Nitriles; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines
chemical_list: D000480:Alkynes; D001386:Azides; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D003300:Copper; C540383:ruxolitinib; D053612:Janus Kinases
keywords: Janus kinase inhibitors; click chemistry; copper-catalyzed azide−alkyne cycloaddition; heterocycles; triazoles