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 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.
Khelili
S
S
Laboratoire de Chimie Pharmaceutique, Institut de Pharmacie, Université Liège, Belgium.
de Tullio
P
P
Lebrun
P
P
Fillet
M
M
Antoine
M H
MH
Ouedraogo
R
R
Dupont
L
L
Fontaine
J
J
Felekidis
A
A
Leclerc
G
G
Delarge
J
J
Pirotte
B
B
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002478:Cells, Cultured; D003497:Cyclic N-Oxides; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004341:Drug Evaluation; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C121899:3-(2'-butylamino)-4H-pyrido(4,3-e)-1,2,4-thiadiazine 1,1-dioxide; D003497:Cyclic N-Oxides; D003499:Cyclic S-Oxides; D015221:Potassium Channels; D011725:Pyridines; D013829:Thiadiazines; C087201:BPDZ 44; D000255:Adenosine Triphosphate