Novel Small Molecule Bradykinin B2 Receptor Antagonists

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• 作者：Christoph Gibson ; Karsten Schnatbaum ; Jochen R. Pfeifer ; Elsa Locardi ; Matthias Paschke ; Ulf Reimer ; Uwe Richter ; Dirk Scharn ; Alexander Faussner ; Thomas Tradler
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：July 23, 2009
• 年：2009
• 卷：52
• 期：14
• 页码：4370-4379
• 全文大小：920K
• 年卷期：v.52,no.14(July 23, 2009)
• ISSN：1520-4804

文摘

Blockade of the bradykinin B₂ receptor provides therapeutic benefit in hereditary angioedema (HAE) and potentially in many other diseases. Herein, we describe the development of highly potent B₂ receptor antagonists with a molecular weight of approximately 500 g/mol. First, known quinoline-based B₂ 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 B₂ receptor antagonists, featuring a hydrogen bond accepting functionality, which presumably interacts with the side chain of Asn-107 of the B₂ receptor. Optimization of the microsomal stability and cytochrome P450 inhibition eventually led to the discovery of the highly potent and orally available B₂ receptor antagonist 52e (JSM10292), which showed the best overall properties.