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Free keywords:
drug discovery, FKBP ligands, cyclization, neutrotropic agents, rational design
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.
