Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib.
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| 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.
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| Authors | Y Jin, C L Smith, L Hu, K M Campanale, R Stoltz, L G Huffman Jr, T A McNearney, X Y Yang, B L Ackermann, R Dean, A Regev, W Landschulz |
| Journal | Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 99 Issue 3 Pg. 274-84 (Mar 2016) ISSN: 1532-6535 [Electronic] United States |
| PMID | 26351780 (Publication Type: Comparative Study, Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2015 The American Society for Clinical Pharmacology and Therapeutics. |
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