Sulfoximine substituted quinazolines for pharmaceutical compositions US 20150005278 (A1): a patent evaluation

ABSTRACT

Mnk1 and Mnk2 are protein kinases responsible for phosphorylating eIF4E, a eukaryotic initiation factor responsible for initiating translation. Inhibiting Mnk1 and Mnk2 could therefore play a role in treating metabolic diseases such as cancer, diabetes, and hyperlipidemia. A wide range of sulfoximine substituted quinazolines were synthesised and evaluated for their Mnk1 and Mnk2 inhibitory activity. Amongst these compounds, 26 quinazolines showed activity against Mnk1 at <100 nM and 54 showed activity against Mnk2 at 1 nM. The results indicate that this scaffold is much more active against Mnk2 than Mnk1. The synthesised compounds may be future drugs in the treatment of metabolic diseases.

KEYWORDS:

• Mnk inhibitors
• Mnk1
• Mnk2
• quinazoline
• sulfoximine

Article highlights

• Sulfoximine substituted quinazolines are potent Mnk1 and Mnk2 inhibitors.

• The sulfoximine substituted quinazoline derivatives were more active against Mnk2 than Mnk1.

• Sulfoximine substituted quinazolines are lead compounds for the treatment of metabolic diseases such as cancer and diabetes.

• The sulfoximine moiety is most easily synthesised with sodium azide and sulphuric acid or o-mesitylenesulfonylhydroxylamine.

• Variation at the 4, 5 and 7 positions lead to a variety of sulfoximine substituted quinazoline derivatives.This box summarizes key points contained in the article.