Quinazoline and phthalazine derivatives as novel melatonin receptor ligands analogues of agomelatine

• Published in: European journal of medicinal chemistry Vol. 189; p. 112078
• Main Authors: Bolteau, Raphaël, Descamps, Florian, Ettaoussi, Mohamed, Caignard, Daniel H., Delagrange, Philippe, Melnyk, Patricia, Yous, Saïd
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.03.2020; Elsevier
• Subjects: Acetamides - chemistry; Acetamides - metabolism; Agomelatine; Agonist; Animals; Chemical Sciences; Chemistry, Medicinal; CHO Cells; Cricetinae; Cricetulus; HEK293 Cells; Humans; Life Sciences & Biomedicine; Ligands; Melatonin receptor; MT1; MT2; Pharmacology & Pharmacy; Phthalazine; Phthalazines - chemistry; Phthalazines - metabolism; Quinazoline; Quinazolines - chemistry; Quinazolines - metabolism; Receptor, Melatonin, MT1 - metabolism; Receptor, Melatonin, MT2 - metabolism; Science & Technology; Structure-Activity Relationship; Agonist; Phthalazine; MLT; AGM; Agomelatine; MT2; MT1; Quinazoline; Melatonin receptor; DESIGN; SERIES; MT1/MT2; RAMELTEON; PHARMACOLOGICAL EVALUATION; MT
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112078

For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT1 and MT2 ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT1 and MT2, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties. [Display omitted] •New quinazoline and phthalazine analogues of agomelatine were prepared•Obtained compounds showed good melatonergic affinity and no 5-HT2C affinity•Quinazoline 11c showed the most interesting results of this series•Phthalazine 20c showed a10 times MT2-selectivity over MT1