ABSTRACT
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.
Subject(s)
Amides/chemistry , Cyclooxygenase Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Phosphoric Acids/chemistry , Phosphoric Acids/chemical synthesis , Prodrugs/chemical synthesis , Sulfonamides/chemical synthesis , Acute Disease , Animals , Carrageenan , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacokinetics , Cyclooxygenase Inhibitors/pharmacology , Dogs , Edema/drug therapy , Half-Life , Humans , Hyperalgesia/drug therapy , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Isoenzymes/antagonists & inhibitors , Male , Membrane Proteins , Pain Measurement , Phosphoric Acids/pharmacokinetics , Phosphoric Acids/pharmacology , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Prostaglandin-Endoperoxide Synthases , Rats , Rats, Wistar , Solubility , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , WaterABSTRACT
New spin-state-selective (S3) NMR pulse sequences exclusively applying cross-polarization schemes to achieve optimum homonuclear and heteronuclear 1H-X coherence transfer are reported for the simple and accurate measurement of the magnitude and sign of heteronuclear coupling constants for samples at natural abundance. The proposed spin-edited HCP-TOCSY experiments are based on clean heteronuclear S3 excitation, generated by simultaneous co-addition of two independent in-phase and anti-phase components created during the mixing heteronuclear J-cross-polarization (HCP) step, which is finally transferred to other protons by a conventional homonuclear TOCSY mechanism. Selective 1D and non-selective 2D approaches for the easy determination of long-range proton-carbon and proton-nitrogen coupling constants on any protonated and non-protonated heteronuclei are presented and discussed for several organic molecules.
