Novel Small Molecule Bradykinin B2 Receptor Antagonists

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.