Potent Nonpeptide Antagonists of the Bradykinin B1 Receptor: Structure−Activity Relationship Studies with Novel Diaminochroman Carboxamides

The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure−activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the β-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38...