Endothelin antagonists: evaluation of 2,1,3-benzothiadiazole as a methylendioxyphenyl bioisoster.
The methylendioxyphenyl group is present in a number of endothelin receptor antagonists thus far reported. By means of a Kohonen neural network we discovered with a benzothiadiazole a bioisosteric replacement instead. This group should be devoid of the negative metabolic interactions with cytochrome P450 ascribed to methylendioxyphenyl in vivo. The synthesis of a potent benzothiadiazole analogue EMD 122801 together with in vitro studies of different methylendioxyphenyl, benzothiadiazole and benzofurazan derivatives is described.
Mederski
W W
WW
Merck KGaA, Preclinical Pharmaceutical Research, Darmstadt, Germany. mederski@merck.de
Osswald
M
M
Dorsch
D
D
Anzali
S
S
Christadler
M
M
Schmitges
C J
CJ
Wilm
C
C
D004149:Dioxoles / Q000737:chemistry* / Q000494:pharmacology; D016232:Endothelins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology
D004149:Dioxoles; D016232:Endothelins; D013830:Thiadiazoles; C116437:methylendioxyphenyl; C015700:benzo-1,2,3-thiadiazole