273213-65-3Relevant articles and documents
Novel potassium channel opener prodrugs with a slow onset and prolonged duration of action
Horino, Haruhiko,Mimura, Tetsuya,Kobayashi, Syozo,Ohta, Masahiro,Kubo, Hideo,Ito, Kuniko,Tsumura, Mitsuyoshi,Kitagawa, Masayuki
, p. 490 - 495 (2007/10/03)
(-)-(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.