7-Phenyl-imidazoquinolin-4(5H)-one derivatives as selective and orally available mPGES-1 inhibitors

Tomoya Shiro; Keisuke Kakiguchi; Hirotada Takahashi; Hidetaka Nagata; Masanori Tobe

doi:10.1016/j.bmc.2013.03.069

7-Phenyl-imidazoquinolin-4(5H)-one derivatives as selective and orally available mPGES-1 inhibitors

Bioorg Med Chem. 2013 Jun 1;21(11):2868-78. doi: 10.1016/j.bmc.2013.03.069. Epub 2013 Apr 6.

Authors

Tomoya Shiro¹, Keisuke Kakiguchi, Hirotada Takahashi, Hidetaka Nagata, Masanori Tobe

Affiliation

¹ Drug Research Division, Dainippon Sumitomo Pharma. Co. Ltd, 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-0022, Japan.

PMID: 23623673
DOI: 10.1016/j.bmc.2013.03.069

Abstract

To identify compounds with strong mPGES-1 inhibitory activity and clear in vitro ADME profile, we optimized the lead compound 1 by carrying our substitutions at the C(7)- and C(8)-positions. Replacement of the bromine atom of 1 with various substituents led to identification of the phenyl group as the best C(7)-substituent giving strong inhibitory activity with good in vitro ADME profile. Further SAR examination on both the C(2)- and the C(7)-phenyl groups provided compound 39 as the best candidate for further development. Compound 39 exhibited strong mPGES-1 inhibitory activity (IC50=4.1 nM), potent cell-based functional activity (IC50=33 nM) with good mPGES-1 selectivity (over 700-fold), excellent in vitro ADME profile, and good oral absorption in rat PK study.

MeSH terms

Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics*
Biological Availability
Cytochrome P-450 Enzyme System / chemistry
Cytochrome P-450 Enzyme System / metabolism
Drug Discovery
Drug Stability
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics*
HEK293 Cells
Humans
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacology
Inhibitory Concentration 50
Prostaglandin-E Synthases
Prostaglandin-Endoperoxide Synthases / chemistry*
Prostaglandin-Endoperoxide Synthases / metabolism
Quinolones / chemical synthesis*
Quinolones / chemistry
Quinolones / pharmacology
Rats
Sensitivity and Specificity
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Enzyme Inhibitors
Imidazoles
Quinolones
Cytochrome P-450 Enzyme System
Prostaglandin-Endoperoxide Synthases
Prostaglandin-E Synthases
Ptges protein, rat