A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a Ki of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (greater than 8000) in culture.

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In our efforts to develop novel small-molecule inhibitors for the NOD-like receptor family pyrin-domain-containing 3 (NLRP3) inflammasome as potential disease-modifying agents to treat neurological disorders including multiple sclerosis (MS), a hydroxyl sulfonamide analogue JC-171 has been rationally designed and biologically characterized both in vitro and in vivo. Our studies established that JC-171 dose dependently inhibited LPS/ATP-induced interleukin-1β (IL-1β) release from J774A.1 macrophages with an IC50 of 8.45 ± 1.56 μM. Selective inhibition of the NLRP3 inflammasome induced IL-1β release by this compound was also confirmed using mouse bone-marrow-derived macrophages and LPS-challenged mice in vivo. Furthermore, immunoprecipitation study revealed that JC-171 interfered with NLRP3/ASC interaction induced by LPS/ATP stimulation. More importantly, JC-171 treatment delayed the progression and reduced the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, in both prophylactic and therapeutic settings. This coincided with blocking of IL-1β production and a pathogenic Th17 response. Collectively, these results suggest that JC-171 is a selective NLRP3 inflammasome inhibitor with biological activity in vivo, thus strongly encouraging further development of this lead compound as a potential therapeutic agent for human MS.

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