1-(Thienylalkyl)imidazole-2(3H)-thiones as potent competitive inhibitors of dopamine .beta.-hydroxylase

Abstract

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.

The Local Minima Method (LMM) of Pharmacophore Determination: A Protocol for Predicting the Bioactive Conformation of Small, Conformationally Flexible Molecules

“…Thiophene is generally considered to be a bioisostere of phenyl. 19 In the paper by McCarthy et al, 20 which discussed the MMD series of inhibitors, it was speculated that thiophene may not be acting as a bioisostere because of conformational differences between thiophene and 4-hydroxy-phenyl based inhibitors in their postulated bioactive conformations. The compounds and their activities are listed in Table 5.…”

“…The IC 50 values for the MMD DBH inhibitors were determined using an oxygen electrode method. 20 The IC 50 's of the SKF inhibitors were measured by a UV absorption method 15 which produced values higher than would normally be expected based on the K i values which were determined. While the assays were different, both used the same commercially available bovine DBH (Sigma).…”

“…Bioisosteric replacement of the phenyl group with thiophene 19 by McCarthy et al 20 at Marion Merrell Dow Inc. (MMD) resulted in a series of 11 1-(thienylalkyl)imidazole-2(3H)-thiones which were potent competitive inhibitors of dopamine β-hydroxylase (Table 1, rows [1][2][3][4][5][6][7][8][9][10][11][12]. The structure-activity relationships of the two different series showed an interesting trend.…”

Synthesis and biological evaluation ofS-[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5-HT1Areceptors by positron emission tomography (PET)

“…23 The synthesis of the labelling precursor 3 was accomplished in 50% yield by cyclization of a diethyl acetal derivative (2) with potassium thiocyanate under acidic conditions, which is a common method for the synthesis of 2-mercaptoimidazoles (Scheme 3). 24,25 Amino acetal 2 has been obtained by alkylation of compound 1 with bromoacetaldehyde diethyl acetal. The reaction was performed using an excess of primary amine 1 to avoid overalkylation.…”

New Inhibitors of Laccase and Tyrosinase by Examination of Cross-Inhibition between Copper-Containing Enzymes

“…The cellular level of copper is much lower than that of zinc, and copper-containing proteins are much fewer in number than zinc-containing proteins. The small molecules that inhibit coppercontaining enzymes are scarce, except for those that inhibit tyrosinase and dopamine-βhydroxylase (DBH) [9][10][11][12][13]. The FDA has approved hydroquinone as a depigmenting agent through the inhibition of tyrosinase [3].…”