Sphingosine 1-phosphate (S1P) lyase, which degrades S1P into trans-hexadecenal and phosphoethanolamine, has been described as a potential target for autoimmune disorders, like rheumatoid arthritis 1) and multiple sclerosis 2). 1-[4-(1R,2S,3R)-1,2,3,4-Tetrahydroxybutyl]-1H-imidazol-2-yl]ethanone (THI) known as a functional S1P lyase inhibitor, that reduces S1P lyase activity within in vivo but not in vitro assays, shows lymphopenia in blood as well as the resulting immunosuppression in rodents 3). Recently, a functional S1P lyase inhibitor (E)-1-[4-(1R,2S,3R)-1,2,3,4-tetrahydroxybutyl]-1H-imidazol-2-yl]ethanone oxime (LX2931) which is derived from THI, has been reported to exhibit oral efficacy in mice collagen- induced arthritis model 2). Moreover, LX2931 has advanced into phase II clinical trials for the treatment of rheumatoid arthritis 4). To identify a novel oral active S1P lyase inhibitor, we set out to conduct a medicinal chemistry study starting from THI as a lead compound. In this study, host versus graft reaction model (HVGR) and peripheral lymphocyte reduction assay in rodents were utilized as systematical in vivo screening to evaluate the potential S1P lyase inhibitory activity of the synthesized compounds. As a result, a functional S1P lyase inhibitor 1-[4(5)-hydroxymethyl)-1H- imidazole-2-yl]ethanone (1) was identified as a promising compound suitable for further evaluation toward a clinical candidate. Compound 1 showed a remarkable reduction in circulating lymphocyte counts in mice, rats, and monkeys at oral doses of 3 mg/kg and more. In addition, compound 1 also demonstrated efficacy in mice experimental autoimmune encephalomyelitis model with ED50 = 89 mg/kg. Furthermore, it was revealed that 1 was phosphorylated to provide [2-acetyl-1H-imidazole-4(5)-yl]methoxyphosphate (2) in vivo, which exhibited S1P lyase inhibition in a cell-free assay at submicromolar concentrations 5). These results suggest that the immunosuppressive activity of 1 would be attributed to direct S1P lyase inhibition by the active metabolite 2. In this presentation, detailed structure-activity relationship (SAR), synthesis, and biological evaluations of 1 and 2 will be discussed. Reference 1) J. Med. Chem., 52, 3941 (2009). J. Med. Chem., 53, 8650 (2010). 2) PLoS One, 8, e59630 (2013). J. Med. Chem., 57, 5074 (2014). 3) Science, 309, 1735 (2005). 4) Lexicon Pharmaceuticals Inc. website. 5) Submitting.

Discovery of 1-[4(5)-(hydroxymethyl)-1H-imidazol-2-yl]ethanone: Novel oral active sphingosine 1-phosphate lyase inhibitor

251st National Meeting (2016)

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