Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib. Issue 3 (25th November 2015)

• Record Type: Journal Article
• Authors: Jin, Y; Smith, CL; Hu, L; Campanale, KM; Stoltz, R; Huffman, LG; McNearney, TA; Yang, XY; Ackermann, BL; Dean, R; Regev, A; Landschulz, W
• Is Part Of: Clinical pharmacology & therapeutics. Volume 99:Issue 3(2016:Mar.)
• Page Start: 274
• Page End: 284
• Publication Date: 2015-11-25
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1002/cpt.260
• Languages: English
• ISSNs: 0009-9236

Abstract

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.