However, Nurr1 has remarkable constitutive transcriptional inducer activity and, therefore, can be modulated in a bidirectional fashion. While Nurr1 agonists have been established as chemical tools , Nurr1 inhibition with small molecules is poorly explored. Especially for nuclear receptors with high intrinsic -ligand independent -activity like the NR4A and NR1F (retinoic acid receptorrelated orphan receptors (RORs)) subfamilies, blocking baseline activity with inverse agonists is of interest for biological studies and, potentially, therapeutic purposes. While beneficial effects of inverse agonists have been demonstrated for RORγ in the context of autoimmune diseases , therapeutic potential of inhibiting Nurr1 activity remains elusive and chemical tools to explore this field are needed. We have developed a first intermediately potent inverse Nurr1 agonist (5) from a fragment screening hit and discovered a few non-steroidal anti-inflammatory drugs (NSAIDs) including oxaprozin (6) as direct inhibitors of Nurr1 activity. Importantly, 5 and analogues comprised preference for blocking Nurr1 monomer activity while 6 diminished the activity of Nurr1 as monomer, homodimer and heterodimer . Together, the chemotypes of 5 and 6 would hence form an attractive pair of tools to study biological effects of pharmacological Nurr1 blockade potentially discriminating monomer and dimer mediated effects. However, oxaprozin (6) is a weak inverse Nurr1 agonist (IC50 40 µM) and additionally modulates the retinoid X receptor, another member of the nuclear receptor family and the heterodimer partner of Nurr1, preventing its use as an in vitro chemical tool. Bioisosteres 48-50 of the carboxylic acid in 6 were prepared from phenylbenzylketone 61 which was cyclized with succinonitrile 96 to oxazole 97 in presence of iodine, TfOH and oxidant oxone according to a slightly modified procedure by Wu et al. (Scheme 5). The 1H-tetrazole in 48 was obtained directly from the propanenitrile 97 via tin-catalyzed [3+2] cycloaddition using azidotri-n-butyltin(IV). Compound 49 was prepared over two steps from nitrile 97 according to a published procedure . First, the reaction of nitrile 97 with hydroxylamine provided hydroxyamidine 98 in good yield. The oxadiazolone 49 was then formed by refluxing 98 with CDI in THF. For compound 50, hydrolysis of nitrile 97 under basic conditions provided oxaprozin (6) , which was subsequently coupled with methanesulfoneamide in the presence of EDC and 4-DMAP .