ABSTRACT
To assess the safety, tolerability, and pharmacology of LY3023703, a microsomal prostaglandin E synthase 1 (mPGES1) inhibitor, a multiple ascending dose study was conducted. Forty-eight subjects received LY3023703, celecoxib (400 mg), or placebo once daily for 28 days. Compared with placebo, LY3023703 inhibited ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2 ) synthesis 91% and 97% on days 1 and 28, respectively, after 30-mg dosing, comparable to celecoxib's effect (82% inhibition compared to placebo). Unlike celecoxib, which also inhibited prostacyclin synthesis by 44%, LY3023703 demonstrated a maximal increase in prostacyclin synthesis of 115%. Transient elevations of serum aminotransferase were observed in one subject after 30-mg LY3023703 dosing (10× upper limit of normal (ULN)), and one subject after 15-mg dosing (about 1.5× ULN). Results from this study suggest that mPGES1 inhibits inducible PGE synthesis without suppressing prostacyclin generation and presents a novel target for inflammatory pain.
Subject(s)
Celecoxib/pharmacology , Celecoxib/pharmacokinetics , Intramolecular Oxidoreductases/antagonists & inhibitors , Adult , Celecoxib/administration & dosage , Celecoxib/blood , Dinoprostone/biosynthesis , Dose-Response Relationship, Drug , Epoprostenol/biosynthesis , Female , Humans , Male , Middle Aged , Prostaglandin-E Synthases , Young AdultABSTRACT
Nitrogen transfer to glycals: A new method for direct C2-aza-glycosylation with glycal donors has been developed (see scheme), employing the new reagent combination of thianthrene-S-oxide and trifluoroacetic anhydride for glycal activation, in an overall one-pot procedure.
