Publications by authors named "D Caignard"
In our constant search for new successors of agomelatine, we report herein a new series of compounds resulting from bioisosteric modulation of the naphthalene ring. The isoquinoline and tetrahydroisoquinoline derivatives were synthesized and pharmacologically evaluated. This isosteric replacement of the naphthalene group of agomelatine has led to potent agonist and partial agonist compounds with nanomolar melatonergic binding affinities.
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- A new family of melatonin receptor ligands was developed by modifying the pharmacokinetic properties of Agomelatine, introducing quinazoline and phthalazine scaffolds with specific chemical groups.
- The biological activity of the newly synthesized ligands showed that they could achieve strong binding affinity, particularly as potent agonists, when compared to Agomelatine.
- While the inclusion of two nitrogen atoms led to a decrease in receptor affinity, these compounds still demonstrated favorable pharmacokinetic properties, indicating potential for further development.
Article Synopsis
- Researchers designed nitrogen heterocycles based on α-ethoxyphenylpropionic acid derivatives to target PPARα/γ receptors for treating type 2 diabetes (T2D).
- Among the compounds tested, 6-Benzoyl-benzothiazol-2-one demonstrated the best results after modifications, leading to a specific stereoisomer with an excellent in vitro pharmacological profile.
- This compound was identified as a potent full PPARγ agonist and a weak partial agonist for PPARα, showing effectiveness in reducing triglycerides, glucose, and insulin levels in ob/ob mice without causing significant weight gain, classifying it as a selective PPARγ modulator (SPPARγM).
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.
View Article and Find Full Text PDFDual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol () and polycerasoidin () and their derivatives for novel drug development. Nine semisynthetic derivatives were prepared from the natural polycerasoidol () and polycerasoidin (), which were evaluated for PPARα, -γ, -δ and retinoid X receptor-α activity in transactivation assays.
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