title: Synthesis and biological evaluation of substituted imidazoquinoline derivatives as mPGES-1 inhibitors.
abstract: We have previously reported 7-bromo-2-(2-chrolophenyl)-imidazoquinolin-4(5H)-one (1) as a novel potent mPGES-1 inhibitor. To clarify the essential functional groups of 1 for inhibition of mPGES-1, we investigated this compound structure-activity relationship following substitution at the C(4)-position and N-alkylation at the N(1)-, the N(3)-, and the N(5)-positions of 1. To prepare the target compounds, we established a good methodology for selective N-alkylation of the imidazoquinolin-4-one, that is, selective alkylation of 1 at the N(3)- and N(5)-positions was achieved by use of an appropriate base and introduction of a protecting group at the nitrogen atom in the imidazole part, respectively. Replacement of the C(4)-oxo group with nitrogen- or sulfur- linked substituents gave decreased inhibitory activity for mPGES-1, and introduction of alkyl groups on the nitrogen atom at the N(1)-, the N(3)-, and the N(5)-positions resulted in even larger loss of inhibitory activity. These results revealed that the C(4)-oxo group, and the hydrogen atoms at the N(5)-position and the imidazole part were the best substituents.
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors: Tomoya
authors: T
authors: Shiro
authors: Keisuke
authors: K
authors: Kakiguchi
authors: Hirotada
authors: H
authors: Takahashi
authors: Hidetaka
authors: H
authors: Nagata
authors: Masanori
authors: M
authors: Tobe
mesh_terms: D000478:Alkylation; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D011804:Quinolines; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases