1,4‐Pyrazolyl‐Containing SAFit‐Analogues are Selective FKBP51 Inhibitors With Improved Ligand Efficiency and Drug‐Like Profile

The FK506 binding protein 51 (FKBP51) is an appealing drug target due to its role in several diseases such as depression, anxiety, chronic pain and obesity. Towards this, selectivity versus the close homolog FKBP52 is essential. However, currently available FKBP51‐selective ligands such as SAFit2 are too large and lack drug‐like properties. Here, we present a structure activity relationship (SAR) analysis of the pipecolic ester moiety of SAFit1 and SAFit2, which culminated in the discovery of the 1,4‐pyrazolyl derivative 23 d, displaying a binding affinity of 0.077 μM for FKBP51, reduced molecular weight (541.7 g/mol), lower hydrophobicity (cLogP=3.72) and higher ligand efficiency (LE=0.25). Cocrystal structures revealed the importance of the 1,4‐ and 1,3,4‐ substitution patterns of the pyrazole ring versus the 1,4,5 arrangement.

SAFit2 is the current gold standard for the selective inhibition of the FK506-binding protein 51 (FKBP51). While being a useful tool compound, its poor physicochemical profile and large size prevent SAFit2 from being pursued as a drug candidate. In the present structure-activity relationship (SAR) study, the newly discovered 1,4-pyrazolyl analogue 23 d retains selective binding to FKBP51 and shows an improved drug-like profile with lower lipophilicity (cLogP), reduced molecular weight (MW) and increased ligand efficiency compared to SAFit2.