Design and Synthesis of Novel Sulfonamide-Containing Bradykinin hB2 Receptor Antagonists. 1. Synthesis and SAR of α,α-Dimethylglycine Sulfonamides

We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol. Exp. Ther. 2005, 616−623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing human B2 receptor (hB2R) antagonists. Here we report, in detail, how this family of compounds was designed, synthesized, and optimized to provide a group of products with subnanomolar affinity for the hB2R and high in vivo potency after topical administration to the respiratory tract. The series was designed on the basis of indications from the X-ray structures of the key structural motifs A and B present in known antagonists and is characterized by the presence of an α,α-dialkyl amino acid. The first lead (17) of the series was submitted to extensive chemical work to elucidate the structural requirements to increase hB2 receptor affinity and antagonist potency in bioassays expressing the human B2 receptor (hB2R). The following structural features were selected:  a 2,4-dimethylquinoline moiety and a piper...