title: Rapid, Structure-Based Exploration of Pipecolic Acid Amides as Novel Selective Antagonists of the FK506-Binding Protein 51.
abstract: The FK506-binding protein 51 (FKBP51) is a key regulator of stress hormone receptors and an established risk factor for stress-related disorders. Drug development for FKBP51 has been impaired by the structurally similar but functionally opposing homologue FKBP52. High selectivity between FKBP51 and FKBP52 can be achieved by ligands that stabilize a recently discovered FKBP51-favoring conformation. However, drug-like parameters for these ligands remained unfavorable. In the present study, we replaced the potentially labile pipecolic ester group of previous FKBP51 ligands by various low molecular weight amides. This resulted in the first series of pipecolic acid amides, which had much lower molecular weights without affecting FKBP51 selectivity. We discovered a geminally substituted cyclopentyl amide as a preferred FKBP51-binding motif and elucidated its binding mode to provide a new lead structure for future drug optimization.
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry , Kraepelinstrasse 2, 80804 Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Gaali
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry , Kraepelinstrasse 2, 80804 Munich, Germany.
authors.forename: Xixi
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry , Kraepelinstrasse 2, 80804 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hähle
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry , Kraepelinstrasse 2, 80804 Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sippel
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry , Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bracher
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry , Kraepelinstrasse 2, 80804 Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D016501:Neurites / Q000187:drug effects; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D012307:Risk Factors; D013329:Structure-Activity Relationship; D022021:Tacrolimus Binding Proteins / Q000187:drug effects*; D014961:X-Ray Diffraction; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000577:Amides; D010875:Pipecolic Acids; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C031345:pipecolic acid