Pharmacodynamic Comparison of LY3023703, a Novel Microsomal Prostaglandin E Synthase 1 Inhibitor, With Celecoxib

被引：58

作者：

Jin, Y. ^{[1
]}

Smith, C. L. ^{[2
]}

Hu, L. ^{[1
]}

Campanale, K. M. ^{[1
]}

Stoltz, R. ^{[3
]}

Huffman, L. G., Jr. ^{[1
]}

McNearney, T. A. ^{[1
]}

Yang, X. Y. ^{[1
]}

Ackermann, B. L. ^{[1
]}

Dean, R. ^{[1
]}

Regev, A. ^{[1
]}

Landschulz, W. ^{[1
]}

机构：

[1] Eli Lilly & Co, Indianapolis, IN 46285 USA

[2] Eli Lilly & Co, Lilly UK, Windlesham, Surrey, England

[3] Covance Clin Res Unit, Evansville, IN USA

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2016年 / 99卷 / 03期

关键词：

BLOOD-PRESSURE; CYCLOOXYGENASE-2; INHIBITORS; PROSTACYCLIN; BIOSYNTHESIS; ATHEROGENESIS; DELETION; HUMANS; MICE;

D O I：

10.1002/cpt.260

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 E-2 (PGE(2)) 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 (10x upper limit of normal (ULN)), and one subject after 15-mg dosing (about 1.5x ULN). Results from this study suggest that mPGES1 inhibits inducible PGE synthesis without suppressing prostacyclin generation and presents a novel target for inflammatory pain.

引用

页码：274 / 284

页数：11

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