Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship.
Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).
Jönsson
Stig
S
Active Biotech Research AB, Box 724, SE-220 07 Lund, Sweden. stig.jonsson@activebiotech.com
Andersson
Gunnar
G
Fex
Tomas
T
Fristedt
Tomas
T
Hedlund
Gunnar
G
Jansson
Karl
K
Abramo
Lisbeth
L
Fritzson
Ingela
I
Pekarski
Olga
O
Runström
Anna
A
Sandin
Helena
H
Thuvesson
Ingela
I
Björk
Anders
A
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D004285:Dogs; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D005260:Female; D006912:Hydroxyquinolines / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000276:Adjuvants, Immunologic; D006912:Hydroxyquinolines; D015363:Quinolones; C045282:roquinimex; C476223:laquinimod