Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1 R, 2 S, 3 R)-1, 2, 3, 4-tetrahydroxybutyl)-1 H-imidazol-2-yl …
JT Bagdanoff, MS Donoviel, A Nouraldeen… - Journal of medicinal …, 2010 - ACS Publications
JT Bagdanoff, MS Donoviel, A Nouraldeen, M Carlsen, TC Jessop, J Tarver, S Aleem…
Journal of medicinal chemistry, 2010•ACS PublicationsSphingosine 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 …
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 …
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.
ACS Publications