New water-soluble sulfonylphosphoramidic acid derivatives of the COX-2 selective inhibitor cimicoxib. A novel approach to sulfonamide prodrugs.
The synthesis and pharmacological evaluation of new water-soluble phosphoramidate derivatives of the COX-2 selective inhibitor cimicoxib (4) are described. The sulfonylphosphoramidic acid derivative 10 was converted to 4 in human plasma and showed excellent in vivo activity in the rat carrageenan-edema test. Pharmacokinetic evaluation in dogs indicated that 10 behaved as a prodrug, immediately converting to 4 and giving an identical profile to that of the parent compound. These results represent the first description of phosphoramidic acids as prodrugs for the sulfonamido group. Compound 10 also exhibited an important and sustained analgesic effect in the hyperalgesia test in rats and a high aqueous solubility at pH higher than 7. This profile led to the selection of 10 (UR-14048) for further development in the parenteral treatment of acute pain.
Almansa
Carmen
C
Research Center, Grupo Uriach. Av. Camí Reial, 51-57, E-08184, Palau-Solità i Plegamans, Spain. chem-almansa@uriach.com
Bartrolí
Javier
J
Belloc
Jordi
J
Cavalcanti
Fernando L
FL
Ferrando
Rosa
R
Gómez
Luis A
LA
Ramis
Isabel
I
Carceller
Elena
E
Merlos
Manuel
M
García-Rafanell
Julián
J
D000208:Acute Disease; D000577:Amides / Q000737:chemistry*; D000818:Animals; D002351:Carrageenan; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004487:Edema / Q000188:drug therapy; D006207:Half-Life; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008565:Membrane Proteins; D010147:Pain Measurement; D010756:Phosphoric Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014867:Water
D000577:Amides; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D008565:Membrane Proteins; C493523:N-(4-(4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl)phenylsulfonyl)phosphoramidic acid; D010756:Phosphoric Acids; D011355:Prodrugs; D013449:Sulfonamides; D014867:Water; D002351:Carrageenan; C011067:phosphoramidic acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C493522:cimicoxib