Novel potassium channel opener prodrugs with a slow onset and prolonged duration of action.
(-)-(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-carbo nitrile 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.
Horino
H
H
New Product Research Laboratories II, Daiichi Pharmaceutical Company, Ltd., Tokyo, Japan.
Mimura
T
T
Kobayashi
S
S
Ohta
M
M
Kubo
H
H
Ito
K
K
Tsumura
M
M
Kitagawa
M
M
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006339:Heart Rate / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008956:Models, Chemical; D008958:Models, Molecular; D015221:Potassium Channels / Q000187:drug effects*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
D000959:Antihypertensive Agents; D015221:Potassium Channels; D011355:Prodrugs; D019806:Cromakalim