ABSTRACT
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).
Subject(s)
Adjuvants, Immunologic/chemical synthesis , Autoimmune Diseases/drug therapy , Quinolones/chemical synthesis , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Animals , Dogs , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Female , Hydroxyquinolines/therapeutic use , Mice , Mice, Inbred C57BL , Quinolones/chemistry , Quinolones/therapeutic use , Structure-Activity RelationshipABSTRACT
A fast and simple approach to novel cyclic isothioureas and related guanidine derivatives is presented in this study. The construction of the central basic scaffolds is achieved solely by the application of microwave-assisted chemistry, without any need of activating agents or protecting group manipulations. The product formation of various substituted guanidines from the corresponding isothiouronium salts was controlled by the nucleophilicity of the counterion and influenced by the reaction temperature. Further, a new fast-track access to tetrahydropyrimidin-2-ylamines was developed.
