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キーワード:
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要旨:
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.
