Affiliation:
1. Department of Chemistry and Biochemistry Clemens-Schöpf-Institute Technical University Darmstadt Alarich-Weiss Straße 4 64287 Darmstadt Germany
2. Present address Dr. Michael Bauder InfectoPharm Arzneimittel und Consilium GmbH Von-Humboldt-Str.1 64646 Heppenheim Germany
3. Department of Translational Research in Psychiatry Max Planck Institute of Psychiatry 80804 Munich Germany
4. Present address Dr. Steffen Gaali Roche Diagnostics GmbH Nonnenwald 2 82377 Penzberg
5. Center for Synthetic Biology Technical University Darmstadt Germany
Abstract
AbstractThe 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.