STING antagonists, synthesized Povarov-Doebner type multicomponent reaction.

The cGAS-STING axis plays an important role in protecting higher organisms against invading pathogens or cancer by promoting the production of cytokines and interferons. However, persistent or uncontrolled activation of this pathway could lead to inflamed environments, which is detrimental to the host in the long run. Persistent activation of STING is known to be the cause of STING-associated vasculopathy with onset in infancy (SAVI) and activated STING is believed to play important roles in worsening various diseased states, such as traumatic brain injury, diabetic kidney disease and colitis. Thus, antagonists of STING could play important roles in managing various inflammatory diseases. Herein, we report the discovery of small molecule STING inhibitors, and analogs, which are facilely synthesized a Povarov-Doebner type three-component reaction involving an amine, ketone, and aldehyde. Structure-activity relationship, SAR, studies indicate that both the 3-pyrazolo[4,3-]quinoline and pyrazole moieties in are critical for STING binding. At concentrations as low as 20 nM, suppressed type-1 interferon expression in both murine RAW macrophages and human THP-1 monocytes upon treatment with 100 μM 2'-3' cGAMP. Compounds containing the 3-pyrazolo[4,3-]quinoline moiety have the potential to be translated into anti-inflammatory compounds STING inhibition.