A new convenient synthetic method and preliminary pharmacological characterization of triazinediones as prokineticin receptor antagonists

• Published in: European journal of medicinal chemistry Vol. 81; pp. 334 - 340
• Main Authors: Congiu, Cenzo, Onnis, Valentina, Deplano, Alessandro, Salvadori, Severo, Marconi, Veronica, Maftei, Daniela, Negri, Lucia, Lattanzi, Roberta, Balboni, Gianfranco
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 23.06.2014; Elsevier
• Subjects: Analgesic activity; Animals; Chemistry, Medicinal; Dose-Response Relationship, Drug; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Pharmacology & Pharmacy; Prokineticin antagonists; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - deficiency; Receptors, G-Protein-Coupled - genetics; Science & Technology; Structure-Activity Relationship; Triazinediones; Triazines - administration & dosage; Triazines - chemical synthesis; Triazines - pharmacology; Triazinediones; Prokineticin antagonists; Analgesic activity; VEGF
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.05.030

A new efficient synthetic method to obtain prokineticin receptor antagonists based on the triazinedione scaffold is described. In this procedure the overall yield improves from 13% to about 54%, essentially for two factors: 1) N-(chlorocarbonyl) isocyanate is no more used, it represents the yield limiting step with an average yield not exceeding 30%. 2) The Mitsunobu reaction is not involved in the new synthetic scheme avoiding the use of time and solvent consuming column chromatography. All synthesized triazinediones were preliminary pharmacologically screened in vivo for their ability to reduce the Bv8-induced thermal hyperalgesia. In this assay all compounds displayed EC50 values in the picomolar–subpicomolar range, some triazinediones containing a 4-halogen substituted benzyl group in position 5 showed the best activity. The analogues containing a 4-fluorine atom (PC-7) and a 4-bromobenzyl group (PC-25) resulted 10 times more potent than the reference PC-1 that bears a 4-ethylbenzyl group. While the 4-trifluoromethylbenzyl substituted analog (PC-27) was 100 times more potent as compared to PC1. [Display omitted] •A new efficient synthetic method to obtain triazinedione derivatives was studied.•In vivo activity of the triazinediones as prokineticin receptor antagonists was assayed.•In vivo ability of the triazinediones to reduce the Bv8-induced thermal hyperalgesia was assayed.•Halogenated triazinediones resulted 10–100 times more potent than the reference non halogenated PC-1.