Novel, selective indole-based ECE inhibitors: Lead optimization via solid-phase and classical synthesis

Brands, Michael; Ergüden, Jens-Kerim; Hashimoto, Kentaro; Heimbach, D.; Schröder, Christian; Siegel, Stephan; Stasch, Johannes‐Peter; Weigand, Stefan

doi:10.1016/j.bmcl.2005.06.085

Cited by 21 publications

(9 citation statements)

References 15 publications

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“…An added goal of the optimization program was to improve the in vitro activity of 6 (IC 50 =1.8 μ M ) by lowering the IC 50 value into the nanomolar range. However, as described earlier,26 variations in the side chains attached to the indole skeleton at the N1 and C5 positions did not give rise to compounds with improved activity. For this reason, it was hypothesized that these moieties bind a corresponding pocket of the enzyme with high affinity.…”

Section: Structure–activity Relationship Studiessupporting

confidence: 63%

“…Clearly, no interaction to Val 565 is possible, as the indole nitrogen atom bears a substituent. However, the 2‐fluoro benzyl substituent is observed to fit tightly into the S3′ pocket, which explains why SAR does not tolerate variations at this position 26. No major interaction is observed for the amide group directly attached to the 2 position of the indole.…”

Section: Structure–activity Relationship Studiesmentioning

confidence: 96%

“…Overall, the model is able to provide a rationale for the observed SAR trends for the indole‐type inhibitors 26. It highlights the pharmacophore character of the central amide group of the bisaryl amide side chain binding to His 732 and Ala 567 of the ECE backbone without interacting directly with the Zn center.…”

Section: Structure–activity Relationship Studiesmentioning

confidence: 96%

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Selective Indole‐Based ECE Inhibitors: Synthesis and Pharmacological Evaluation

et al. 2006

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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.

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Section: Structure–activity Relationship Studiessupporting

confidence: 63%

Section: Structure–activity Relationship Studiesmentioning

confidence: 96%

Section: Structure–activity Relationship Studiesmentioning

confidence: 96%

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Selective Indole‐Based ECE Inhibitors: Synthesis and Pharmacological Evaluation

et al. 2006

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“…In this context recent patents propose to use a novel class of indole-based ECE inhibitors to diminish the production of ET-1 to inhibit bronchoconstriction and pulmonary vasoconstriction in newborn mammals [167,168].…”

Section: Allergic Inflammationmentioning

confidence: 99%

Recent Developments on Endothelin Antagonists as Immunomodulatory Drugs - from Infection to Transplantation Medicine

Nett¹,

Teixeira²,

Candinas³

et al. 2006

PRC

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Endothelin, a potent endogenous vasoconstrictor and mitogen that acts through the ET(A) and ET(B) receptors, has been not only implicated in the regulation of cardiovascular homeostasis but also in inflammatory responses, including that induced by infection and solid organ transplantation. Changes in capillary perfusion and leukocyte recruitment are important features of inflammation. The concentrations of ET are elevated in many forms of inflammation and are especially high in sepsis. The rise in plasma levels of ET during early stages of inflammation may initially have some positive homeostatic effects that might help to maintain vascular tone and blood pressure. However, high levels of ET compromise the appropriate matching of flow to tissue needs and contribute to the pathophysiology of microcirculatory derangements. Attempts at regulating the effects of ET by the use of pharmacological antagonists are complicated by important interactions between the ET(A) and ET(B) receptors. This review highlights findings of recent studies and patents in this area showing that the ET system, apart from being a marker of vascular and tissue injury, is directly involved in the pathophysiology of these disease processes as an immunomodulatory mediator.

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“…1) display a wide range of pharmacological activities and therefore have been explored as a number of potential therapeutic agents [1] e.g. inhibitors of proteases involved in coagulation [2–3], antagonists of G-protein-coupled receptors [4–5], anti-angiogenic compounds [6] and inhibitors of endothelinconverting-enzyme [7]. 5-Alkyl substituted indoles e.g.…”

Section: Introductionmentioning

confidence: 99%