Synthesis of benzopyran derivatives as PPARα and/ or PPARγ activators

Almudena Bermejo (1) , Isabel Barrachina (1) , Noureddine El Aouad (1) , Xavier Franck (2) , Nadia Chahboune (1) , Inmaculada Andreu (1) , Bruno Figadère (3) , Laura Vila (1) , Nathalie Hennuyer (4) , Bart Staels (4) , Catherine Dacquet (5) , Daniel Caignard (5) , María-Jesús Sanz (1) , Diego Cortes (1) , Nuria Cabedo (1)

1 UV - Universitat de València
2 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
3 LabEx LERMIT - Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry]
4 RNMCD - Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011
5 IRIS - Institut de Recherches Internationales Servier [Suresnes]

We describe the synthesis of 26 compounds, small polycerasoidol analogs, that are Lipinski’s rule-of-five compliant. In order to confirm key structural features to activate PPARα and/or PPARγ, we have adopted structural modifications in the following parts: (i) the benzopyran core (hydrophobic nucleus) by benzopyran-4-one, dihydrobenzopyran or benzopyran-4-ol; (ii) the side chain at 2-position by shortening to C3, C4 and C5-carbons versus C-9-carbons of polycerasoidol; (iii) the carboxylic group (polar head) by oxygenated groups (hydroxyl, acetoxy, epoxide, ester, aldehyde) or non-oxygenated motifs (allyl and alkyl). Benzopyran-4-ones 6, 12, 13 and 17 as well as dihydrobenzopyrans 22, 24 and 25 were able to activate hPPARα, whereas benzopyran-4-one (7) with C5-carbons in the side chain exhibited hPPARγ agonism. According to our previous docking studies, SAR confirm that the hydrophobic nucleus (benzopyran-4-one or dihydrobenzopyran) is essential to activate PPARα and/or PPARγ, and the flexible linker (side alkyl chain) should containg at least C5-carbon atoms to activate PPARγ. By contrast, the polar head (“carboxylic group”) tolerated several oxygenated groups but also non-oxygenated motifs. Taking into account these key structural features, small polycerasoidol analogs might provide potential active molecules useful in the treatment of dyslipidemia and/or type 2 diabetes.

Domaines: Chimie

Almudena Bermejo, Isabel Barrachina, Noureddine El Aouad, Xavier Franck, Nadia Chahboune, et al.. Synthesis of benzopyran derivatives as PPARα and/ or PPARγ activators. Bioorganic and Medicinal Chemistry Letters, 2019, 27 (24), pp.115162. ⟨10.1016/j.bmc.2019.115162⟩. ⟨hal-02347291⟩