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

The preparation and the pharmacological evaluation of the R-and S-isomers o f 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, 1,2,4-thiadiazine 1;1-dioxide (BPDZ 44), two potassium channel openers, is described. Their optical puri ty was estimated by means of capillary electrophoresis (R- and S-BPDZ 42) a nd chiral HPLC (R- and S-BPDZ 44). The absolute configuration of each isome r of BPDZ 44 was deduced from crystallographic data. Pharmacological assays performed with the R- and S-isomers of BPDZ 44 revealed only slight differ ences in their activity on pancreatic B-cells but significant differences i n their activity on vascular smooth muscle cells; the R-isomer being sixfol d 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 pa ncreas. 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. (C ) 1999 Published by Elsevier Science Ltd. All rights reserved.