Rachel M Chen, Stefan Emming, Roseanna Cinnamon, Jacob P Cameron, Kate Schroder, Bostjan Kobe, Avril A B Robertson
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The design, synthesis, and biological evaluation of 5,6,7,8-tetrahydropteridines as anti-inflammatory compounds.
The NLRP3 inflammasome is implicated in the pathogenesis of a wide array of inflammatory diseases including cancer, type II diabetes, atherosclerosis, gout, and neurodegenerative disease. Research has shown that Bruton's tyrosine kinase (BTK) is a critical regulator of the NLRP3 inflammasome and that the pharmacological inhibition of BTK using the FDA-approved inhibitor ibrutinib diminishes NLRP3-dependent inflammatory response. Herein, we describe our pursuit towards novel anti-inflammatory compounds using a scaffold-hopping approach. In our drug discovery efforts, we identified 5,6,7,8-tetrahydropteridines as underutilized scaffolds in medicinal chemistry. We report the synthesis of 5,6,7,8-tetrahydropteridines with potential as anti-inflammatory compounds.