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Karsten Schnatbaum,
Marco Schaudt,
Roland Stragies,
Jochen R Pfeifer,
Christoph Gibson,
Elsa Locardi,
Dirk Scharn, Uwe Richter,
Holger Kalkhof,
Klaus Dinkel,
Gunther Zischinsky
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ABSTRACT: Hydroxy urea moieties are introduced as a new class of bradykinin B(1) receptor antagonists. First, the SAR of the lead compound was systematically explored. Subsequent optimization resulted in the identification of several biaryl-based hydroxyurea bradykinin B(1) receptor antagonists with low-nanomolar activity and very high oral bioavailability in the rat.
Bioorganic & medicinal chemistry letters 02/2010; 20(3):1233-6. · 2.65 Impact Factor
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Marco Schaudt,
Elsa Locardi,
Gunther Zischinsky,
Roland Stragies,
Jochen R Pfeifer,
Christoph Gibson,
Dirk Scharn, Uwe Richter,
Holger Kalkhof,
Klaus Dinkel,
Karsten Schnatbaum
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ABSTRACT: The synthesis and SAR of two series of bradykinin B(1) receptor antagonists is described. The benzamide moiety proved to be a suitable replacement for the aryl ester functionality of biaryl based antagonists. In addition, it was found that semicarbazides can effectively replace cyclopropyl amino acids. The compounds with the best overall profile were biaryl semicarbazides which display high antagonistic activity, low Caco-2 efflux and high oral bioavailability in the rat.
Bioorganic & medicinal chemistry letters 12/2009; 20(3):1225-8. · 2.65 Impact Factor
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Gunther Zischinsky,
Roland Stragies,
Marco Schaudt,
Jochen R Pfeifer,
Christoph Gibson,
Elsa Locardi,
Dirk Scharn, Uwe Richter,
Holger Kalkhof,
Klaus Dinkel,
Karsten Schnatbaum
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ABSTRACT: Efforts to find new bradykinin B(1) receptor antagonists identified 2-aminobenzimidazole as a novel core. Subsequent transformation into five-membered diaminoheterocycle derivatives and their synthesis and SAR is described. This resulted in compounds with low nanomolar activity.
Bioorganic & medicinal chemistry letters 12/2009; 20(3):1229-32. · 2.65 Impact Factor
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ABSTRACT: Blockade of the bradykinin B(2) receptor provides therapeutic benefit in hereditary angioedema (HAE) and potentially in many other diseases. Herein, we describe the development of highly potent B(2) receptor antagonists with a molecular weight of approximately 500 g/mol. First, known quinoline-based B(2) receptor antagonists were stripped down to their shared core motif 53, which turned out to be the minimum pharmacophore. Targeted modifications of 53 resulted in the highly water-soluble lead compound 8a. Extensive exploration of its structure-activity relationship resulted in a series of highly potent B(2) receptor antagonists, featuring a hydrogen bond accepting functionality, which presumably interacts with the side chain of Asn-107 of the B(2) receptor. Optimization of the microsomal stability and cytochrome P450 inhibition eventually led to the discovery of the highly potent and orally available B(2) receptor antagonist 52e (JSM10292), which showed the best overall properties.
Journal of Medicinal Chemistry 07/2009; 52(14):4370-9. · 4.80 Impact Factor
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ABSTRACT: A new class of peptidomimetic C5a receptor antagonists characterized by C-terminal amino acids with hydrophobic side chains is presented. Systematic optimization of the first hits led to JPE1375 (36), which was intensively characterized in vitro and in vivo. Compound 36 exhibits high microsomal stability and receptor specificity and is highly active in an immune complex mediated peritonitis model (reverse passive Arthus reaction) in mice.
Bioorganic & Medicinal Chemistry Letters 11/2006; 16(19):5088-92. · 2.55 Impact Factor
