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)

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; David J Augeri

doi:10.1021/jm101183p

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)

J Med Chem. 2010 Dec 23;53(24):8650-62. doi: 10.1021/jm101183p. Epub 2010 Nov 22.

Affiliation

¹ Lexicon Pharmaceuticals, Inc., Princeton, New Jersey 08540, USA.

PMID: 21090716
DOI: 10.1021/jm101183p

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.

Publication types

Clinical Trial, Phase I

MeSH terms

Aldehyde-Lyases / antagonists & inhibitors*
Aldehyde-Lyases / genetics
Animals
Antirheumatic Agents / chemical synthesis*
Antirheumatic Agents / pharmacokinetics
Antirheumatic Agents / pharmacology
Arthritis, Experimental / drug therapy
Arthritis, Experimental / immunology
Arthritis, Experimental / pathology
Blood Pressure / drug effects
Cell Movement
Dogs
Heart Rate / drug effects
Imidazoles / chemical synthesis*
Imidazoles / pharmacokinetics
Imidazoles / pharmacology
Isoxazoles / chemical synthesis*
Isoxazoles / pharmacokinetics
Isoxazoles / pharmacology
Lymphocytes / drug effects
Lymphocytes / physiology
Macaca fascicularis
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Oximes / chemical synthesis*
Oximes / pharmacokinetics
Oximes / pharmacology
Rats
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship

Substances

1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol
1-(4-(1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime
Antirheumatic Agents
Imidazoles
Isoxazoles
Oximes
Aldehyde-Lyases
sphingosine 1-phosphate lyase (aldolase)