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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
24
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pubmed:dateCreated |
2010-12-17
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AleemSaadatS,
pubmed-author:AugeriDavid JDJ,
pubmed-author:BagdanoffJeffrey TJT,
pubmed-author:BednarzMarkM,
pubmed-author:BotejuLakmalL,
pubmed-author:BrooksBarbaraB,
pubmed-author:BrownPhilipP,
pubmed-author:CarlsenMarianneM,
pubmed-author:CarsonKenneth GKG,
pubmed-author:DongLiL,
pubmed-author:DonovielMichael SMS,
pubmed-author:ElyJohnJ,
pubmed-author:FrazierKenny SKS,
pubmed-author:GopinathanSumaS,
pubmed-author:HazelwoodJillJ,
pubmed-author:HeydornWilliam EWE,
pubmed-author:JessopTheodore CTC,
pubmed-author:KimballS DavidSD,
pubmed-author:KramerJeffJ,
pubmed-author:LaiZhongZ,
pubmed-author:LayekSumanS,
pubmed-author:MainAlanA,
pubmed-author:MoranLiamL,
pubmed-author:NouraldeenAmrA,
pubmed-author:OraveczTamasT,
pubmed-author:OwusuIris BIB,
pubmed-author:SonnenburgWilliam KWK,
pubmed-author:TarverJamesJ,
pubmed-author:WilsonAlanA,
pubmed-author:YalamanchiliPadmajaP,
pubmed-author:ZhangHaimingH
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pubmed:issnType |
Electronic
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pubmed:day |
23
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pubmed:volume |
53
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
8650-62
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pubmed:meshHeading |
pubmed-meshheading:21090716-Aldehyde-Lyases,
pubmed-meshheading:21090716-Animals,
pubmed-meshheading:21090716-Antirheumatic Agents,
pubmed-meshheading:21090716-Arthritis, Experimental,
pubmed-meshheading:21090716-Blood Pressure,
pubmed-meshheading:21090716-Cell Movement,
pubmed-meshheading:21090716-Dogs,
pubmed-meshheading:21090716-Heart Rate,
pubmed-meshheading:21090716-Imidazoles,
pubmed-meshheading:21090716-Isoxazoles,
pubmed-meshheading:21090716-Lymphocytes,
pubmed-meshheading:21090716-Macaca fascicularis,
pubmed-meshheading:21090716-Male,
pubmed-meshheading:21090716-Mice,
pubmed-meshheading:21090716-Mice, Inbred C57BL,
pubmed-meshheading:21090716-Mice, Inbred DBA,
pubmed-meshheading:21090716-Oximes,
pubmed-meshheading:21090716-Rats,
pubmed-meshheading:21090716-Rats, Sprague-Dawley,
pubmed-meshheading:21090716-Stereoisomerism,
pubmed-meshheading:21090716-Structure-Activity Relationship
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pubmed:year |
2010
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pubmed:articleTitle |
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).
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pubmed:affiliation |
Lexicon Pharmaceuticals, Inc., Princeton, New Jersey 08540, USA.
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pubmed:publicationType |
Journal Article,
Clinical Trial, Phase I
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