Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's disease

  • Bioorg Med Chem Lett. 2019 Apr 1;29(7):929-932. doi: 10.1016/j.bmcl.2019.01.024.
Dominique Lesuisse  1 ,  André Malanda  2 ,  Jean-François Peyronel  2 ,  Yannick Evanno  2 ,  Patrick Lardenois  2 ,  Danielle De-Peretti  2 ,  Pierre-Yves Abécassis  3 ,  Pascal Barnéoud  4 ,  Pascale Brunel  5 ,  Marie-Claude Burgevin  6 ,  Céline Cegarra  4 ,  Florian Auger  2 ,  Amélie Dommergue  2 ,  Corinne Lafon  7 ,  Luc Even  2 ,  Joanna Tsi  2 ,  Thy Phuong Hieu Luc  2 ,  Antonio Almario  2 ,  Anne Olivier  6 ,  Marie-Noëlle Castel  8 ,  Véronique Taupin  4 ,  Thomas Rooney  4 ,  Xavier Vigé  6
Affiliations
  • 1. Rare and Neurologic Disease Research, Sanofi, 1 av Pierre Brossolette, Chilly Mazarin F-91935, France. Electronic address: [email protected].
  • 2. Medicinal Chemistry, Sanofi, 1 av Pierre Brossolette, Chilly Mazarin F-91385, France.
  • 3. DMPK, Sanofi, 13 quai Jules Guesde, Vitry-sur-Seine F-94403, France.
  • 4. Rare and Neurologic Disease Research, Sanofi, 1 av Pierre Brossolette, Chilly Mazarin F-91935, France.
  • 5. Preclinical Safety, Sanofi, 3, digue d' Alfortville, Alfortville F-94140, France.
  • 6. Translational Science, Sanofi, 1 av Pierre Brossolette, Chilly Mazarin F-91385, France.
  • 7. CNS Department, Sanofi, 195 route d'Espagne, F-31036 Toulouse, France.
  • 8. CNS Department, 13, quai Jules Guesde, F-94403 Vitry-sur-Seine Cedex, France.
PMID: 30773432 DOI: 10.1016/j.bmcl.2019.01.024
Abstract

In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson's Disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringent structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.