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)

被引：99

作者：

Bagdanoff, Jeffrey T. ^{[1
]}

Donoviel, Michael S. ^{[2
]}

Nouraldeen, Amr ^{[2
]}

Carlsen, Marianne ^{[1
]}

Jessop, Theodore C. ^{[1
]}

Tarver, James ^{[1
]}

Aleem, Saadat ^{[1
]}

Dong, Li ^{[1
]}

Zhang, Haiming ^{[1
]}

Boteju, Lakmal ^{[1
]}

Hazelwood, Jill ^{[2
]}

Yan, Jack ^{[1
]}

Bednarz, Mark ^{[1
]}

Layek, Suman ^{[1
]}

Owusu, Iris B. ^{[2
]}

Gopinathan, Suma ^{[2
]}

Moran, Liam ^{[2
]}

Lai, Zhong ^{[1
]}

Kramer, Jeff ^{[2
]}

Kimball, S. David ^{[1
]}

Yalamanchili, Padmaja ^{[1
]}

Heydorn, William E. ^{[1
]}

Frazier, Kenny S. ^{[2
]}

Brooks, Barbara ^{[2
]}

Brown, Philip ^{[2
]}

Wilson, Alan ^{[2
]}

Sonnenburg, William K. ^{[2
]}

Main, Alan ^{[1
]}

Carson, Kenneth G. ^{[1
]}

Oravecz, Tamas ^{[2
]}

Augeri, David J. ^{[1
]}

机构：

[1] Lexicon Pharmaceut Inc, Princeton, NJ 08540 USA

[2] Lexicon Pharmaceut Inc, The Woodlands, TX 77381 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 24期

关键词：

PROTEIN-COUPLED-RECEPTOR; SPHINGOSINE-1-PHOSPHATE LYASE; LYMPHOCYTE SEQUESTRATION; FTY720; IMMUNOSUPPRESSANT; IDENTIFICATION; GENERATION; APOPTOSIS; MYRIOCIN; IMMUNITY;

D O I：

10.1021/jm101183p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-tetrahydroxy-butyl)-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.

引用

页码：8650 / 8662

页数：13

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