title: 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).
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.
authors.affiliation: Lexicon Pharmaceuticals, Inc., Princeton, New Jersey 08540, USA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Bagdanoff
authors.forename: Michael S
authors.initials: MS
authors.lastname: Donoviel
authors.forename: Amr
authors.initials: A
authors.lastname: Nouraldeen
authors.forename: Marianne
authors.initials: M
authors.lastname: Carlsen
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Jessop
authors.forename: James
authors.initials: J
authors.lastname: Tarver
authors.forename: Saadat
authors.initials: S
authors.lastname: Aleem
authors.forename: Li
authors.initials: L
authors.lastname: Dong
authors.forename: Haiming
authors.initials: H
authors.lastname: Zhang
authors.forename: Lakmal
authors.initials: L
authors.lastname: Boteju
authors.forename: Jill
authors.initials: J
authors.lastname: Hazelwood
authors.forename: Jack
authors.initials: J
authors.lastname: Yan
authors.forename: Mark
authors.initials: M
authors.lastname: Bednarz
authors.forename: Suman
authors.initials: S
authors.lastname: Layek
authors.forename: Iris B
authors.initials: IB
authors.lastname: Owusu
authors.forename: Suma
authors.initials: S
authors.lastname: Gopinathan
authors.forename: Liam
authors.initials: L
authors.lastname: Moran
authors.forename: Zhong
authors.initials: Z
authors.lastname: Lai
authors.forename: Jeff
authors.initials: J
authors.lastname: Kramer
authors.forename: S David
authors.initials: SD
authors.lastname: Kimball
authors.forename: Padmaja
authors.initials: P
authors.lastname: Yalamanchili
authors.forename: William E
authors.initials: WE
authors.lastname: Heydorn
authors.forename: Kenny S
authors.initials: KS
authors.lastname: Frazier
authors.forename: Barbara
authors.initials: B
authors.lastname: Brooks
authors.forename: Philip
authors.initials: P
authors.lastname: Brown
authors.forename: Alan
authors.initials: A
authors.lastname: Wilson
authors.forename: William K
authors.initials: WK
authors.lastname: Sonnenburg
authors.forename: Alan
authors.initials: A
authors.lastname: Main
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Carson
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
authors.forename: David J
authors.initials: DJ
authors.lastname: Augeri
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D002465:Cell Movement; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010091:Oximes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C555224:1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol; C555223:1-(4-(1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime; D018501:Antirheumatic Agents; D007093:Imidazoles; D007555:Isoxazoles; D010091:Oximes; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)