title: Rational design and asymmetric synthesis of potent and neurotrophic ligands for FK506-binding proteins (FKBPs).
abstract: To create highly efficient inhibitors for FK506-binding proteins, a new asymmetric synthesis for pro-(S)-C(5) -branched [4.3.1] aza-amide bicycles was developed. The key step of the synthesis is an HF-driven N-acyliminium cyclization. Functionalization of the C(5)  moiety resulted in novel protein contacts with the psychiatric risk factor FKBP51, which led to a more than 280-fold enhancement in affinity. The most potent ligands facilitated the differentiation of N2a neuroblastoma cells with low nanomolar potency.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich (Germany).
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pomplun
authors.forename: Yansong
authors.initials: Y
authors.lastname: Wang
authors.forename: Alexander
authors.initials: A
authors.lastname: Kirschner
authors.forename: Christian
authors.initials: C
authors.lastname: Kozany
authors.forename: Andreas
authors.initials: A
authors.lastname: Bracher
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
mesh_terms: D053961:Azabicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D053961:Azabicyclo Compounds; D008024:Ligands; D022021:Tacrolimus Binding Proteins
keywords: FKBP ligands; cyclization; drug discovery; neurotrophic agents; rational design