Synthesis and biological evaluation of substituted imidazoquinoline derivatives as mPGES-1 inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 7; pp. 2068 - 2078
• Main Authors: Shiro, Tomoya, Kakiguchi, Keisuke, Takahashi, Hirotada, Nagata, Hidetaka, Tobe, Masanori
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2013; Elsevier
• Subjects: Alkylation; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; HEK293 Cells; Humans; hydrogen; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoquinoline; Intramolecular Oxidoreductases - antagonists & inhibitors; Intramolecular Oxidoreductases - metabolism; Life Sciences & Biomedicine; mPGES-1; nitrogen; PGE2; Pharmacology & Pharmacy; Physical Sciences; Prostaglandin-E Synthases; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Science & Technology; Selective alkylation; structure-activity relationships; PGE2; mPGES-1; Imidazoquinoline; Selective alkylation; PROSTAGLANDIN E-2 SYNTHASE; MICE LACKING; PGE
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.01.018

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.