1-(Thienylalkyl)imidazole-2(3H)-thiones as potent competitive inhibitors of dopamine beta-hydroxylase.
1-(2-Thienylalkyl)imidazole-2(3H)-thiones (5a-k) are competitive inhibitors of dopamine beta-hydroxylase (DBH) and demonstrate the utility of thiophene in the design of potent competitive inhibitors of this enzyme. The structure-activity relationships for these compounds are discussed and compared with those of 1-phenylalkyl-imidazole-2(3H)-thiones (1). With the aid of molecular modeling, an idealized active-site conformer is proposed and an explanation for the difference in activity between the phenyl (1) and thienyl (5) DBH inhibitors is presented. The difference in activity is consistent with our proposal that thiophene may not always be a bioisostere for phenyl. The inhibitor of most interest, 1-[2-(2-thienyl)ethyl]imidazole-2(3H)-thione (5g), was selected for study in the spontaneously hypertensive rat. The changes in dopamine and norepinephrine levels that resulted from oral administration of 5g correlated with the reduction of blood pressure.
McCarthy
J R
JR
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Matthews
D P
DP
Broersma
R J
RJ
McDermott
R D
RD
Kastner
P R
PR
Hornsperger
J M
JM
Demeter
D A
DA
Weintraub
H J
HJ
Whitten
J P
JP
D000313:Adrenal Medulla / Q000201:enzymology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects*; D002417:Cattle; D003198:Computer Simulation; D004298:Dopamine / Q000097:blood; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D015394:Molecular Structure; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D012016:Reference Values; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000494:pharmacology
D000959:Antihypertensive Agents; D007093:Imidazoles; D007202:Indicators and Reagents; D013871:Thiones; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine; D009638:Norepinephrine