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Klaus Urbahns,
Michael Härter,
Markus Albers,
Delf Schmidt,
Beatrix Stelte-Ludwig,
Ulf Brüggemeier,
Andrea Vaupel,
Jörg Keldenich,
Klemens Lustig, Hideki Tsujishita,
Christoph Gerdes
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ABSTRACT: Vitronectin receptor (alpha(V)beta(3)) antagonists have been implicated as a possible new treatment of restenosis following balloon angioplasty. In this work we investigate a series of novel arginine mimetic scaffolds leading to new insight of the alpha(V)beta(3)/ligand interaction. Squaric acid amide 10 is a subnanomolar alpha(V)beta(3) antagonist with improved potency on human smooth muscle cell migration.
Bioorganic & Medicinal Chemistry Letters 12/2007; 17(22):6151-4. · 2.55 Impact Factor
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Michael Brands,
Jens-Kerim Ergüden,
Kentaro Hashimoto,
Dirk Heimbach,
Thomas Krahn,
Christian Schröder,
Stephan Siegel,
Johannes-Peter Stasch, Hideki Tsujishita,
Stefan Weigand,
Nagahiro H Yoshida
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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.
ChemMedChem 02/2006; 1(1):96-105. · 3.15 Impact Factor
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ABSTRACT: Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated in a variety of disease states, like restenosis, osteoporosis and cancer. In this work, we present the development of a novel class of biphenyl vitronectin receptor antagonists. Identified from a focused combinatorial library based on para-bromo phenylalanine, these compounds show nanomolar affinity to the vitronectin receptor and display unprecedented SAR. Their binding mode can be rationalized by computational docking studies using the X-ray structure of alpha(V)beta(3).
Bioorganic & Medicinal Chemistry Letters 04/2003; 13(6):1071-4. · 2.55 Impact Factor
