title: Novel hinge-binding motifs for Janus kinase 3 inhibitors: a comprehensive structure-activity relationship study on tofacitinib bioisosteres.
abstract: The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen (Germany), Fax: (+49) 7071-29-5037.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gehringer
authors.forename: Michael
authors.initials: M
authors.lastname: Forster
authors.forename: Ellen
authors.initials: E
authors.lastname: Pfaffenrot
authors.forename: Silke M
authors.initials: SM
authors.lastname: Bauer
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
mesh_terms: D001665:Binding Sites; D006860:Hydrogen Bonding; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053616:Janus Kinase 3
keywords: Janus kinase; bioisosteres; cytokines; inflammation; structure-activity relationships