Structure-Based Discovery of a New Selectivity-Enabling Motif for the FK506-Binding Protein 51

In recent years, the selective inhibition of FKBP51 has
emerged as a possible treatment for chronic pain, obesity-induced
diabetes, or depression. All currently known advanced FKBP51-selective
inhibitors, including the widely used SAFit2, contain a cyclohexyl
residue as a key motif for enabling selectivity over the closest homologue
and anti-target FKBP52. During a structure-based SAR exploration,
we surprisingly discovered thiophenes as highly efficient cyclohexyl
replacement moieties that retain the strong selectivity of SAFit-type
inhibitors for FKBP51 over FKBP52. Cocrystal structures revealed that
the thiophene-containing moieties enable selectivity by stabilizing
a flipped-out conformation of Phe67 of FKBP51. Our best
compound, 19b, potently binds to FKBP51 biochemically
as well as in mammalian cells, desensitize TRPV1 in primary sensory
neurons, and has an acceptable PK profile in mice, suggesting its
use as a novel tool compound for studying FKBP51 in animal models
of neuropathic pain.