2. Academic Validation
  3. Structural Optimization of Oxaprozin for Selective Inverse Nurr1 Agonism

Structural Optimization of Oxaprozin for Selective Inverse Nurr1 Agonism

  • J Med Chem. 2024 Aug 8;67(15):13324-13348. doi: 10.1021/acs.jmedchem.4c01218.
Sabine Willems 1,  Romy Busch 1,  Felix Nawa 1,  Marco Ballarotto 1 2,  Felix F Lillich 3 4,  Till Kasch 1,  Úrsula López-García 1,  Julian A Marschner 1,  Lorena A Rüger 3,  Beatrice Renelt 3,  Julia Ohrndorf 3,  Silvia Arifi 3,  Daniel Zaienne 3,  Ewgenij Proschak 3 4,  Jörg Pabel 1,  Daniel Merk 1 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • 2 Department of Pharmaceutical Sciences, Università degli Studi di Perugia, 06123 Perugia, Italy.
  • 3 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
  • 4 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt, Germany.
PMID: 39081058 DOI: 10.1021/acs.jmedchem.4c01218
Abstract

Nuclear receptor related 1 (Nurr1, NR4A2) is a ligand-sensing transcription factor with neuroprotective and anti-inflammatory roles widely distributed in the CNS. Pharmacological Nurr1 modulation is considered a promising experimental strategy in Parkinson's and Alzheimer's disease but target validation is incomplete. While significant progress has been made in Nurr1 agonist development, inverse agonists blocking the receptor's constitutive activity are lacking. Here we report comprehensive structure-activity relationship elucidation of oxaprozin which acts as moderately potent and nonselective inverse Nurr1 agonist and RXR agonist. We identified structural determinants selectively driving RXR agonism or inverse Nurr1 agonism of the scaffold enabling the development of selective inverse Nurr1 agonists with enhanced potency and strong efficacy.

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