Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib.
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.
Eli Lilly and Company, Indianapolis, Indiana, USA.
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Jin
Eli Lilly and Company, Lilly UK, Windlesham, Surrey, UK.
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Smith
Eli Lilly and Company, Indianapolis, Indiana, USA.
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Hu
Eli Lilly and Company, Indianapolis, Indiana, USA.
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KM
Campanale
Covance Clinical Research Unit, Evansville, Indiana, USA.
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Stoltz
Eli Lilly and Company, Indianapolis, Indiana, USA.
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Huffman
Eli Lilly and Company, Indianapolis, Indiana, USA.
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McNearney
Eli Lilly and Company, Indianapolis, Indiana, USA.
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Yang
Eli Lilly and Company, Indianapolis, Indiana, USA.
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Ackermann
Eli Lilly and Company, Indianapolis, Indiana, USA.
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Dean
Eli Lilly and Company, Indianapolis, Indiana, USA.
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Regev
Eli Lilly and Company, Indianapolis, Indiana, USA.
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Landschulz
D000328:Adult; D000068579:Celecoxib / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D000071876:Prostaglandin-E Synthases; D055815:Young Adult
D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D000068579:Celecoxib; D015232:Dinoprostone