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Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers

par Khelili, Smail;de Tullio, Pascal;Lebrun, Philippe ;Fillet, Marianne;Antoine, Marie-Hélène ;Ouedraogo, Raogo;Dupont, Léon ;Fontaine, Jeanine ;Felekidis, Apostolos;Leclerc, Gérard;Delarge, Jacques;Pirotte, Bernard
Référence Bioorganic & medicinal chemistry, 7, 8, page (1513-1520)
Publication Publié, 1999-08

Article révisé par les pairs

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Résumé :

The preparation and the pharmacological evaluation of the R- and S-isomers of 3-(2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 42) and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 44), two potassium channel openers, is described. Their optical purity was estimated by means of capillary electrophoresis (R- and S-BPDZ 42) and chiral HPLC (R- and S-BPDZ 44). The absolute configuration of each isomer of BPDZ 44 was deduced from crystallographic data. Pharmacological assays performed with the R- and S-isomers of BPDZ 44 revealed only slight differences in their activity on pancreatic B-cells but significant differences in their activity on vascular smooth muscle cells; the R-isomer being sixfold more potent than its corresponding S-isomer. The R-isomer of BPDZ 42 was shown to be more potent than its corresponding S-isomer on the endocrine pancreas. S-BPDZ 44 as well as R- and S-BPDZ 42 were found to exhibit tissue selectivity for the pancreatic versus the vascular smooth muscle tissue. Copyright (C) 1999.