Selective Indole‐Based ECE Inhibitors: Synthesis and Pharmacological Evaluation

Abstract

Inhibition of the metalloprotease ECE-1 may be beneficial for the treatment of coronary heart disease, cancer, renal failure, and urological disorders. A novel class of indole-based ECE inhibitors was identified by high throughput screening. Optimization of the original screening lead structure 6 led to highly potent inhibitors such as 11, which bears a bisaryl amide moiety linked to the indole C2 position through an amide group. Docking of 11 into a model structure of ECE revealed a unique binding mode in which the Zn center of the enzyme is not directly addressed by the inhibitor, but key interactions are suggested for the central amide group. Testing of the lead compound 6 in hypertensive Dahl S rats resulted in a decrease in blood pressure after an initial period in which the blood pressure remained unchanged, most probably the result of ET-1 already present. Indole derivative 6 also displays a cardio-protective effect in a mouse model of acute myocardial infarction after oral administration. The more potent chloropyridine derivative 9 antagonizes big-ET-1-induced increase in blood pressure in rats at intravenous administration of 3 mg kg-1. All ECE inhibitors of the indole class showed high selectivity for ECE over related metalloproteases such as NEP and ACE. Therefore, these compounds might have further potential as drugs for the treatment of coronary heart diseases.

Pharmacokinetic and pharmacodynamic properties of SOL1: A novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme

“…This in vitro profile is comparable to the one reported for phosphoramidon. The latter compound has been widely used both in vitro and in vivo as a non-selective NEP/ECE inhibitor (IC 50 for NEP 4-30 nM; IC 50 for ECE 1-4 μM) (Brands et al, 2006;Jeng et al, 2002). It should be noted that these IC 50 values are based on the use of recombinant enzymes in cell free conditions.…”

“…Benzazepine acid derivatives are well known NEP inhibitors (Brands et al, 2006;Jeng et al, 2002). The chemical name of SOL1 3-(methylamino)propyl](methyl)amino]-4-oxobutanoic acid].…”

Endothelins and their receptors in cancer: Identification of therapeutic targets

“…Agonist availability in endosomes, regulated by ECE-1, was observed to control β-arrestin-dependent signaling of endocytosed G protein-coupled receptors. Chemical screening of ECE antagonists has identified several interesting leads, including CGS35066 [63], SM19712 [64], RO67-7447 [65], and various indole-based compounds [66] with nM IC 50 values. Kirkby et al .…”

Synthesis and Evaluation of 5-Chloro-2-Methoxy-N-(4-Sulphamoylphenyl) Benzamide Derivatives as Anti-cancer Agents

“…On the other hand, various N- (4-sulphamoylphenyl)benzamide containing compounds have demonstrated a range of pharmacological activities including, anti-bacterial [16], inhibition of glucose stimulated insulin release [17], sirtuin-2 deacetylase [18] and viral integrase [19], anti-HIV [20] and other activities that associated with the inhibition of metalloprotease endothelin-converting enzyme and carbonic anhydrase [21][22][23]. However the anti-cancer potential of the N-(4-sulphamoylphenyl)benzamide derivatives has not been fully explored.…”