Design and Synthesis of Novel Sulfonamide-Containing Bradykinin hB2 Receptor Antagonists. 1. Synthesis and SAR of α,α-Dimethylglycine Sulfonamides
Design and Synthesis of Novel Sulfonamide-Containing Bradykinin hB2 Receptor Antagonists. 1. Synthesis and SAR of α,α-Dimethylglycine Sulfonamides
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DOI：
10.1021/jm060137l
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发表时间：
2006-05
影响因子：
7.3
通讯作者：
D. Fattori;C. Rossi;C. I. Fincham;M. Berettoni;F. Calvani;F. Catrambone;P. Felicetti;Martina Gensini;R. Terracciano;M. Altamura;A. Bressan;S. Giuliani;C. Maggi;S. Meini;C. Valenti;L. Quartara
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文献类型：
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作者：
D. Fattori;C. Rossi;C. I. Fincham;M. Berettoni;F. Calvani;F. Catrambone;P. Felicetti;Martina Gensini;R. Terracciano;M. Altamura;A. Bressan;S. Giuliani;C. Maggi;S. Meini;C. Valenti;L. Quartara
我们最近发表了MEN 16132的广泛的体内药理学表征（J. Pharmacol. Exp. Ther. 2005，616 - 623; Eur. J. Pharmacol. 2005，528，7），其是含磺酰胺的人B2受体（hB 2 R）拮抗剂的成员。在这里，我们报告，在详细的，这个家庭的化合物是如何设计，合成和优化，以提供一组产品与subnanomolar的hB 2 R的亲和力和高的局部给药后的体内效力的呼吸道。该系列是根据已知拮抗剂中存在的关键结构基序A和B的X射线结构的指示设计的，其特征在于存在α，α-二烷基氨基酸。对该系列的第一个先导化合物（17）进行了广泛的化学工作，以阐明在表达人B2受体（hB 2 R）的生物测定中增加hB 2受体亲和力和拮抗剂效力的结构要求。选择了以下结构特征：2，4-二甲基喹啉部分和胡椒基。
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...