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

Autor: Buffa V; Department of Chemistry and Biochemistry Clemens-Schöpf-Institute, Technical University Darmstadt, Alarich-Weiss Straße 4, 64287, Darmstadt, Germany.; Present address Dr. Michael Bauder, InfectoPharm Arzneimittel und Consilium GmbH, Von-Humboldt-Str.1, 64646, Heppenheim, Germany., Meyners C; Department of Chemistry and Biochemistry Clemens-Schöpf-Institute, Technical University Darmstadt, Alarich-Weiss Straße 4, 64287, Darmstadt, Germany.; Present address Dr. Michael Bauder, InfectoPharm Arzneimittel und Consilium GmbH, Von-Humboldt-Str.1, 64646, Heppenheim, Germany., Sugiarto WO; Department of Chemistry and Biochemistry Clemens-Schöpf-Institute, Technical University Darmstadt, Alarich-Weiss Straße 4, 64287, Darmstadt, Germany.; Present address Dr. Michael Bauder, InfectoPharm Arzneimittel und Consilium GmbH, Von-Humboldt-Str.1, 64646, Heppenheim, Germany., Bauder M; Department of Chemistry and Biochemistry Clemens-Schöpf-Institute, Technical University Darmstadt, Alarich-Weiss Straße 4, 64287, Darmstadt, Germany.; Present address Dr. Michael Bauder, InfectoPharm Arzneimittel und Consilium GmbH, Von-Humboldt-Str.1, 64646, Heppenheim, Germany., Gaali S; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804, Munich, Germany.; Present address Dr. Steffen Gaali, Roche Diagnostics GmbH, Nonnenwald 2, 82377, Penzberg., Hausch F; Department of Chemistry and Biochemistry Clemens-Schöpf-Institute, Technical University Darmstadt, Alarich-Weiss Straße 4, 64287, Darmstadt, Germany.; Present address Dr. Michael Bauder, InfectoPharm Arzneimittel und Consilium GmbH, Von-Humboldt-Str.1, 64646, Heppenheim, Germany.; Center for Synthetic Biology, Technical University Darmstadt, Germany.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Sep 02; Vol. 19 (17), pp. e202400264. Date of Electronic Publication: 2024 Jul 08.
DOI: 10.1002/cmdc.202400264
Abstrakt: 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.
(© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
Externí odkaz: