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

Dominique Lesuisse; André Malanda; Jean-François Peyronel; Yannick Evanno; Patrick Lardenois; Danielle De-Peretti; Pierre-Yves Abécassis; Pascal Barnéoud; Pascale Brunel; Marie-Claude Burgevin; Céline Cegarra; Florian Auger; Amélie Dommergue; Corinne Lafon; Luc Even; Joanna Tsi; Thy Phuong Hieu Luc; Antonio Almario; Anne Olivier; Marie-Noëlle Castel; Véronique Taupin; Thomas Rooney; Xavier Vigé

doi:10.1016/j.bmcl.2019.01.024

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. Epub 2019 Jan 30.

Authors

Dominique Lesuisse¹, André Malanda², Jean-François Peyronel², Yannick Evanno², Patrick Lardenois², Danielle De-Peretti², Pierre-Yves Abécassis³, Pascal Barnéoud⁴, Pascale Brunel⁵, Marie-Claude Burgevin⁶, Céline Cegarra⁴, Florian Auger², Amélie Dommergue², Corinne Lafon⁷, Luc Even², Joanna Tsi², Thy Phuong Hieu Luc², Antonio Almario², Anne Olivier⁶, Marie-Noëlle Castel⁸, Véronique Taupin⁴, Thomas Rooney⁴, Xavier Vigé⁶

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.

MeSH terms

Animals
Cell Line
Cricetinae
Drug Discovery
Gene Expression Regulation / drug effects
Homeodomain Proteins / metabolism
Interleukin-1beta / genetics
Interleukin-1beta / metabolism
Mice
Microglia / drug effects
Molecular Structure
Neurons / drug effects
Neuroprotective Agents / chemical synthesis*
Neuroprotective Agents / pharmacology*
Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
Parkinson Disease / drug therapy*
Rats
Retinoid X Receptors / genetics
Retinoid X Receptors / metabolism

Substances

Homeodomain Proteins
Interleukin-1beta
Neuroprotective Agents
Not protein, mouse
Nr4a2 protein, mouse
Nuclear Receptor Subfamily 4, Group A, Member 2
Retinoid X Receptors