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.
ChemMedChem. 2024 Sep 2;19(17):e202400264. doi: 10.1002/cmdc.202400264. Epub 2024 Jul 8.
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.
FK506 结合蛋白 51（FKBP51）因其在抑郁症、焦虑症、慢性疼痛和肥胖等多种疾病中的作用而成为一个有吸引力的药物靶点。为此，相对于紧密同源的 FKBP52 的选择性至关重要。然而，目前可用的 FKBP51 选择性配体，如 SAFit2，太大且缺乏类药性。在这里，我们对 SAFit1 和 SAFit2 的哌啶酯部分进行了结构活性关系（SAR）分析，最终发现了 1,4-吡唑基衍生物 23d，对 FKBP51 的结合亲和力为 0.077μM，分子量降低（541.7g/mol），疏水性降低（cLogP=3.72），配体效率提高（LE=0.25）。晶体结构揭示了吡唑环的 1,4-和 1,3,4-取代模式相对于 1,4,5 排列的重要性。
