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1. Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932)

Author

Jeffrey T, Bagdanoff, Michael S, Donoviel, Amr, Nouraldeen, Marianne, Carlsen, Theodore C, Jessop, James, Tarver, Saadat, Aleem, Li, Dong, Haiming, Zhang, Lakmal, Boteju, Jill, Hazelwood, Jack, Yan, Mark, Bednarz, Suman, Layek, Iris B, Owusu, Suma, Gopinathan, Liam, Moran, Zhong, Lai, Jeff, Kramer, S David, Kimball, Padmaja, Yalamanchili, William E, Heydorn, Kenny S, Frazier, Barbara, Brooks, Philip, Brown, Alan, Wilson, William K, Sonnenburg, Alan, Main, Kenneth G, Carson, Tamas, Oravecz, and David J, Augeri

Subjects
Male, Imidazoles, Blood Pressure, Stereoisomerism, Isoxazoles, Arthritis, Experimental, Rats, Mice, Inbred C57BL, Rats, Sprague-Dawley, Macaca fascicularis, Mice, Structure-Activity Relationship, Dogs, Cell Movement, Heart Rate, Mice, Inbred DBA, Antirheumatic Agents, Oximes, Animals, Lymphocytes, Aldehyde-Lyases
Abstract

Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. Medicinal chemistry efforts targeting S1PL by direct in vivo evaluation of synthetic analogues of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI, 1) led to the discovery of 2 (LX2931) and 4 (LX2932). The immunological phenotypes observed in S1PL deficient mice were recapitulated by oral administration of 2 or 4. Oral dosing of 2 or 4 yielded a dose-dependent decrease in circulating lymphocyte numbers in multiple species and showed a therapeutic effect in rodent models of rheumatoid arthritis (RA). Phase I clinical trials indicated that 2, the first clinically studied inhibitor of S1PL, produced a dose-dependent and reversible reduction of circulating lymphocytes and was well tolerated at dose levels of up to 180 mg daily. Phase II evaluation of 2 in patients with active rheumatoid arthritis is currently underway.

Published
2010

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