Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics

Abstract

The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure–activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and in vivo settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.

Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists

“…To estimate the pharmacological relevance of these activities and probe the potential of these compounds for SOSA, we recorded full dose-response curves on the respective targets ( Table 1 ). Oxaprozin was confirmed as an RXR agonist [ 22 ] with intermediate potency, and tianeptine exhibited PPARδ agonism with considerable activation efficacy. Bortezomib and mycophenolic acid activated RAR with low micromolar EC 50 values despite weak activation efficacy.…”

“…All four drugs, therefore, are attractive leads for SOSA. For oxaprozin, this concept has already been implemented successfully leading to the development of highly potent and selective RXR agonists [ 22 ].…”

“…To obtain molecular insights into RAR modulation by bortezomib and mycophenolic acid as well as the PPARδ agonism of tianeptine, we evaluated their interactions by molecular docking. Oxaprozin was omitted as a crystal structure of an analogue with RXRα and has been solved (pdb ID: 7b9o) [ 22 ].…”

Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1

“…Further purification was performed by column chromatography (n-hexane/EtOAc 5:1) to yield 18 as a colorless solid (355 mg, 59%). 1 1H-Indole-3-propan-1-one (22). Et 2 AlCl (309 mg, 2.56 mmol, 1.50 equiv) was added to a solution of 58 (200 mg, 1.71 mmol, 1.00 equiv) in CH 2 Cl 2 (10 mL) at 0 °C.…”

“…Additionally, we have discovered several nonsteroidal anti-inflammatory drugs such as 2 and 3 as direct Nurr1 modulators (Chart ). However, 1–3 mainly target other macromolecules and signaling pathways − than Nurr1 with higher potency and can only serve as early tools for functional studies on Nurr1. Novel Nurr1 ligands are hence needed to probe the therapeutic potential of Nurr1 in neurodegeneration and other pathologies.…”