Synthesis and quantitative structure-activity relationships of anticonvulsant 2,3,6-triaminopyridines.

Autor: Seydel JK; Borstel Research Institute, Germany., Schaper KJ, Coats EA, Cordes HP, Emig P, Engel J, Kutscher B, Polymeropoulos EE
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 1994 Sep 16; Vol. 37 (19), pp. 3016-22.
DOI: 10.1021/jm00045a005
Abstrakt: The synthesis of 2,3,6-triaminopyridine derivatives, representing a unique chemical structure for anticonvulsants, is described. The synthetic program was performed (a) to identify more potent analogs, (b) to determine structural properties controlling potency as well as neurotoxicity, and (c) to reduce the requirements for animal testing. As a result, besides other structural properties, the overall molecular lipophilicity (log k', octanol-coated column) explained changes in anticonvulsant potency and neurotoxicity. Mimicking the interaction of the amphiphilic triaminopyridines with biological membranes, NMR experiments in the presence of lecithin vesicles were conducted in order to measure the phospholipid-binding parameter log delta (1/T2). Replacement of log k' with log delta (1/T2) in the correlation analysis afforded a more significant equation describing the anticonvulsant activity of 21 derivatives.
Databáze: MEDLINE