A new convenient synthetic method and preliminary pharmacological characterization of triazinediones as prokineticin receptor antagonists.
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.
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, I-09124 Cagliari, Italy.
Cenzo
C
Congiu
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, I-09124 Cagliari, Italy. Electronic address: vonnis@unica.it.
Valentina
V
Onnis
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, I-09124 Cagliari, Italy.
Alessandro
A
Deplano
Department of Chemical and Pharmaceutical Sciences, University of Ferrara, I-44100 Ferrara, Italy.
Severo
S
Salvadori
Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, I-00185 Rome, Italy.
Veronica
V
Marconi
Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, I-00185 Rome, Italy.
Daniela
D
Maftei
Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, I-00185 Rome, Italy.
Lucia
L
Negri
Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, I-00185 Rome, Italy.
Roberta
R
Lattanzi
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, I-09124 Cagliari, Italy. Electronic address: gbalboni@unica.it.
Gianfranco
G
Balboni
D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D013329:Structure-Activity Relationship; D014227:Triazines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*
C525015:PKR1 protein, mouse; C525016:PKR2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D014227:Triazines
Analgesic activity; Prokineticin antagonists; Triazinediones