Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E₂ synthase-1 inhibitors

Tomoya Shiro; Hirotada Takahashi; Keisuke Kakiguchi; Yoshifumi Inoue; Keiki Masuda; Hidetaka Nagata; Masanori Tobe

doi:10.1016/j.bmcl.2011.11.015

Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E₂ synthase-1 inhibitors

Bioorg Med Chem Lett. 2012 Jan 1;22(1):285-8. doi: 10.1016/j.bmcl.2011.11.015. Epub 2011 Nov 11.

Authors

Tomoya Shiro¹, Hirotada Takahashi, Keisuke Kakiguchi, Yoshifumi Inoue, Keiki Masuda, 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: 22137787
DOI: 10.1016/j.bmcl.2011.11.015

Abstract

The imidazoquinoline derivative 1 was found as a novel mPGES-1 inhibitor. Optimization of 1 led to the identification of the 2-chlorophenyl group at the C(2)-position and the quinolone structure at the C(4)-position. Compound 33, the most potent synthesized compound, showed excellent mPGES-1 inhibition (IC(50)=9.1nM) with high selectivity (>1000-fold) over both COX-1 and COX-2.

MeSH terms

Ammonia / chemistry
Animals
Chemistry, Pharmaceutical / methods
Cyclooxygenase 1 / biosynthesis
Cyclooxygenase 2 / biosynthesis
Drug Design
Enzyme Inhibitors / pharmacology*
Humans
Inhibitory Concentration 50
Intramolecular Oxidoreductases / antagonists & inhibitors*
Mice
Microsomes / enzymology*
Models, Chemical
Prostaglandin-E Synthases
Quinolones / chemistry*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Quinolones
Ammonia
Cyclooxygenase 1
Cyclooxygenase 2
Intramolecular Oxidoreductases
PTGES protein, human
Prostaglandin-E Synthases
Ptges protein, mouse