Chemical and Pharmaceutical Bulletin p. 490 - 495 (2000)
Update date:2022-09-26
Topics:
Horino, Haruhiko
Mimura, Tetsuya
Kobayashi, Syozo
Ohta, Masahiro
Kubo, Hideo
Ito, Kuniko
Tsumura, Mitsuyoshi
Kitagawa, Masayuki
(-)-(3S,4R,1'R,6'S)-4-(4-Benzyl-5-oxo-3,4-diazabicyclo[4.1.0.]hept-2-en- 2-yloxy)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and its derivatives with a modified benzyl group were synthesized with the objective of discovering novel ATP-sensitive potassium channel openers (PCOs) with a slow onset of action and a reduced tendency to induce tachycardia. Among the compounds synthesized, 4-(2-chlorobenzyl) derivative 5bB had potent hypotensive activity in spontaneously hypertensive rats (SHRs). In addition, compound 5bB showed the desired pharmacological profile with a slow onset and long duration of action and induction of only mild tachycardia. Compound 5bB was found to be quantitatively metabolized in rats to give active des-2- chlorobenzyl derivative 6B. These results suggest that the incorporation of an N-benzyl group is a useful method for the preparation of prodrugs, the function of which is to delay the onset and prolong the duration of action of the active substance.
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